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PURPOSE: To investigate and compare how patients with diabetes mellitus and doctors rate the importance of outcomes used as part of composite endpoints in clinical diabetes trials. Secondly, to compare the ratings of outcomes between patients with low and high education. METHODS: Using a pre-piloted questionnaire, patients with diabetes and doctors working with diabetes were asked to rate the importance of 36 different outcomes commonly used in trials assessing intervention effects in patients with diabetes. The respondents were asked to rate individual outcomes as being either critical, of major importance, of moderate importance, or of minor importance. RESULTS: The study population consisted of 139 patients with a mean age of 56.6 years and an average duration of diabetes for 13.6 years and 45 doctors with a mean time of practice of 19.6 years. There was no difference between patients’ and doctors’ rating of risk of mortality and non-fatal myocardial infarction, and percutaneous coronary intervention (all p-values > 0.34). Non-fatal stroke, admission for heart failure or angina was perceived more severely by patients compared to doctors (all p-values < 0.03). Patients rated risk of foot-ulcers, amputations and quality of life as more important compared to doctors (p-values < 0.01). CONCLUSION: The current study suggest that patients and doctors weigh some diabetic outcomes used as part of composite endpoints in clinical diabetes trials differently. These findings call for more studies on patient reported outcomes and patient education for improved personal care. HIGHLIGHTS: • We performed this study to assess how patients and practicing physicians rate the importance of outcomes commonly used in diabetes trials. • We found that patients and doctors rate the importance of some outcomes used in clinical diabetes trials differently. • These findings suggest that shared decision making is pivotal when taking clinical decisions and that future diabetes studies incorporate end points relevant to both patients and clinicians and do not combine end points which are not equally important.

Introduction Patients with pituitary adenomas undergoing transsphenoidal surgery require pre- and post-surgery examination of pituitary hormones. There is currently no consensus on how to evaluate the adrenal axis post-surgery. The aims of this study were to investigate factors that may predict postoperative adrenal insufficiency (AI) and to investigate the overall effect of transsphenoidal surgery on pituitary function. Methods One hundred and forty-three consecutive patients who had undergone transsphenoidal surgery for pituitary adenomas were included. Data on tumour size, pituitary function pre-surgery, plasma basal cortisol measured within 48 h post-surgery and pituitary function 6 months post-surgery were collected. Patients with AI prior to surgery, perioperative glucocorticoid treatment, Cushing’s disease and no re-evaluation after 1 month were excluded (n = 93) in the basal cortisol analysis. Results Low plasma basal cortisol post-surgery, tumour size and previous pituitary surgery were predictors of AI (all P < 0.05). A basal cortisol cut-off concentration of 300 nmol/L predicted AI 6 months post-surgery with sensitivity and negative predictive value of 100%, specificity of 81% and positive predictive value of 25%. New gonadal, thyroid and adrenal axis insufficiencies accounted for 2, 10 and 10%, respectively. The corresponding recovery rates were 17, 7 and 24%, respectively Conclusion Transsphenoidal surgery had an overall beneficial effect on pituitary endocrine function. Low basal plasma cortisol measured within 48 h after surgery, tumour size and previous surgery were identified as risk factors for AI. Measurement of basal cortisol post-surgery may help to identify patients at risk of developing AI.

The use of electroconvulsive therapy (ECT) in cochlear implant (CI) users is debatable. Currently, no consensus statement exists about the safety for the patients and the implants. Here, we present a summary of the existing literature on ECT in CI users, consisting of 4 case reports and a cadaveric study. No harm to the patients or the CIs was reported. Based on our review, we have found no evidence to indicate that ECT in CI users is contraindicated.

OBJECTIVE Mitotane is used in the treatment of adrenocortical carcinoma (ACC). Metabolic and hormonal side effects of mitotane, the effect of subsequent treatment with statins and hormones and the effects of discontinuation of mitotane were assessed. PATIENTS AND METHODS Fifty patients were included. Lipid profiles, thyroid hormones, sex hormones and adrenal function from first year of mitotane treatment and after cessation were evaluated. RESULTS After 6 months of mitotane treatment total cholesterol increased from (median) 5.1 (IQR 4.3 to 5.8) to 7.4 (6.2-9.0) mmol/L, p

Aim To assess the metabolic effects of dopamine agonists compared to placebo in randomized controlled clinical trials (RCT) including adults with type 2 diabetes mellitus (T2DM). Materials and methods Eligible trials were identified by searching PubMed, Embase, and CENTRAL. The primary outcomes were HbA1c and serious adverse events (SAE) assessed at longest available follow-up. Secondary outcomes were fasting plasma glucose, adverse events, body weight, hypoglycaemia, and triglycerides. We assessed risk of bias and evaluated the certainty of the evidence with the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results Nine RCTs enrolling 3456 participants were included, six assessed the effect of bromocriptine and three the effect of cabergoline. Dopamine agonists reduced HbA1c with 0.69 SMD (95 % CI = 0.28 to 1.09; p = 0.0008; I2 = 80 %; GRADE: low) compared to placebo. There was no difference in the effect between bromocriptine and cabergoline. Heterogeneity was partly explained by dosage and study duration both inversely associated with effect size. Only one large trial reported SAE and found no difference in risk of SAE (RR = 0.89; 95 % CI = 0.70 to 1.12; p = 0.32) between active intervention and placebo. Secondary outcomes suggested a decrease in fasting plasma glucose and triglycerides and no effect on the remaining outcomes. Conclusion Dopamine agonists reduces HbA1c as well as fasting plasma glucose and triglycerides in patients with T2DM without causing SAE. These data are based on moderate to low quality evidence thus our confidence in the effect estimates is limited. This article is protected by copyright. All rights reserved.

Background: The incidence of small intestinal (SI) and pancreatic neuroendocrine tumors (siNETs and pNETs) seems to have increased. The increased frequency of incidental findings might be a possible explanation. The study aimed to examine (1) changes in incidence and the stage at diagnosis (2010–2011 vs. 2019–2020), (2) changes in the initial indication for diagnostic workup and 3) the differences in stage between incidentally discovered vs. symptomatic disease during the entire study period. Methods: We performed a retrospective study, that includes consecutive siNET and pNET patients referred to the Copenhagen ENETS center of excellence in 2010–2011 and 2019–2020. Results: The annual incidence of siNET per 100,000 increased from 1.39 to 1.84, (p = 0.05). There was no change in the stage at diagnosis, and in both periods approximately 30% of patients were incidentally diagnosed (p = 0.62). Dissemination was found in 72/121 (60%) of symptomatic vs. 22/50 (44%) of incidentally discovered SI tumors in the entire cohort, (p = 0.06). The annual incidence of pNET increased from 0.42 to 1.39 per 100,000, (p &lt, 0.001). The proportion of patients with disseminated disease decreased from 8/21 (38%) to 12/75 (16%), (p = 0.02) and the number of incidental findings increased from 4/21 (19%) to 43/75 (57%), (p = 0.002). More symptomatic patients had disseminated disease compared to patients with incidentally discovered tumors (15/49 (31%) vs. 5/47 (11%), (p = 0.01)). Conclusion: The incidence of siNET and pNETs increased over the past decade. For siNETs, the stage of disease and the distribution of symptomatic vs. incidentally discovered tumors were unchanged between the two periods. Patients with pNETs presented with more local and incidentally discovered tumors in the latter period. Patients with incidentally discovered siNETs had disseminated disease in 44% of the overall cases. The vast majority of incidentally found pNETs were localized.

Background and AimsWeight gain is a major adverse effect of antipsychotic medication, negatively affecting physical and mental well-being. The objective of this study was to explore if dose reduction, discontinuation, switch to a partial agonist, or switch from polypharmacy to monotherapy will lead to weight loss.MethodsControlled and uncontrolled studies reporting the effects of discontinuation, dose reduction, switch to a partial agonist, or switch from polypharmacy to monotherapy on weight were included. Primary outcome was difference in weight compared to maintenance groups based on controlled studies. Secondary outcome was change in weight from initiation of one of the included interventions until follow-up in a pre-post analysis.ResultsWe identified 40 randomized controlled trials and 15 uncontrolled studies including 12,279 individuals. The effect of the interventions, i.e. dose reduction, drug discontinuation, or switch to a partial agonis, reduced the weight with 1.5 kg (95% CI −2.03 to −0.98; P < 0.001) compared to maintenance treatment. The weight change from pre to post was a reduction of 1.13 kg (95% CI −1.36 to −0.90; P < 0.001).ConclusionWe found a significant but small reduction in weight, suggesting that antipsychotic-induced weight gain can be reversed to some degree. Only a few studies were designed to address the question as primary outcome, which limits the generalizability of our findings.

Background The 24-h urinary output of 5-hydroxyindoleacetic acid (5-HIAA) is used to monitor disease progression and treatment responses of neuroendocrine neoplasms (NENs). Several conditions are required for 5-HIAA assay, involving urine collection/preservation and food/drug restrictions. Aim To evaluate the correlation between 5-HIAA concentration in a spot urine sample and the output in a 24-h urine collection, and whether spot urine specimens can replace 24-h collection. Methods Patients with NENs or symptoms suggestive of NENs were asked to provide a separate spot urine at the end of the 24-h urine collection for 5-HIAA assessment. The upper reference limit for 24-h urinary 5-HIAA was 40 µmol/24 h. 5-HIAA measurements in spot urine samples were corrected for variation in urine flow rate by expressing results as a ratio to creatinine concentration. Results We included 136 paired urinary samples for 5-HIAA assessment from 111 patients (100 NENs). The correlation between 5-HIAA values measured in 24-h and spot urines was r = +0.863 (P r = +0.840 (P P P Conclusions The ratio of 5-HIAA to creatinine in a spot urine could replace the measurement of 5-HIAA output in a 24-h urine collection, especially for follow-up of patients with known elevated 5-HIAA levels.

Context Cushing syndrome (CS) is associated with hippocampal atrophy and psychopathology. Objective The primary objective of this systematic review was to assess hippocampal volume (HV) in patients with CS. The secondary objectives were to assess patients’ cognitive functioning, depressive and anxiety symptoms, and quality of life. Data Sources PubMed, Embase, Cochrane, LILACs, and Scopus databases were searched for relevant studies until 1 May 2019. Study Selection Case-control studies comparing patients with CS with healthy control subjects, or studies assessing patients with CS before and after surgery were included. The initial search resulted in 18 studies fulfilling the inclusion criteria. Data Extraction Data extraction regarding all outcomes was performed independently by two reviewers. Quality assessment was assessed with the Newcastle-Ottawa Scale for case-control studies. Data Synthesis Meta-analysis was performed using a random effect model. The right-side HV in patients with CS was reduced by a standard mean difference of 0.68 (95% CI, −1.12 to −0.24; P = 0.002; I2 = 0%) compared with healthy control subjects, but with no increase in HV after surgery. Patients had more depressive symptoms, impaired cognitive functions, and reduced health-related QoL (HRQoL), which all responded favorably to surgery. The data did not support the presence of anxiety in patients with CS. Conclusion An overall reduction of HV in patients with CS was not suggested by the study findings. However, most cognitive domains were significantly affected and responded favorably to surgery. Depressive symptoms and reduced HRQoL were present in patients with CS and improved after surgery.

AIM Randomized clinical trials (RCTs) allocating type 2 diabetes patients to treatment with sodium-glucose transport protein 2 (SGLT-2) inhibitors or placebo have found significant effects on the risk of heart failure and modest effects on mortality. In the wake of the first trials, a number of observational studies have been conducted, some of these reporting a mortality reduction of 50% compared to active comparators. In this review, we systematically assess and compare the results on all-cause mortality, cardiovascular mortality and heart failure hospitalization observed in RCTs with the results obtained in observational studies. METHOD We performed a systematic bibliographical search including cardiovascular outcome trials and observational studies assessing the effect of SGLT-2 inhibitors on mortality and heart failure. RESULTS Seven RCTs and 23 observational studies were included in the current review. The observed heterogeneity between study results for all-cause mortality (p-interaction

BACKGROUND: Plasma chromogranin A (CgA) is related to tumor burden and recommended in the follow-up of patients diagnosed with neuroendocrine tumors (NETs). The use of CgA in the workup of a suspected NET is more questionable.OBJECTIVE: To assess the positive predictive value (PPV) of CgA plasma concentrations above the upper reference limit (URL) in patients with suspected NET.METHOD: Patients referred to the NET Centre, Rigshospitalet, Copenhagen from 2015 to 2019 with clinically suspected NET were included if a CgA measurement was performed prior to referral. The utility of CgA was assessed by comparing pre-referral CgA concentrations to the outcome of a thorough workup. In 47 selected cases with continuously unexplained elevated CgA concentrations, a processing-independent analysis (PIA) for CgA was performed.RESULTS: A total of 197 patients were included. NET was ultimately diagnosed in 25 patients. CgA plasma concentrations were above the URL (elevated) in 19/25 patients diagnosed with NET. In total, 167/197 had elevated CgA concentrations at referral. The positive predictive value (PPV) of elevated CgA concentration was 11% (19/167). Proton pump inhibitor (PPI) treatment was identified as the possible cause of CgA elevation in 55/148 patients with falsely elevated CgA. CgA concentration was normal in 28/47 patients when using PIA.CONCLUSION: Our data do not support using measurement of CgA for screening when NET is suspected since the PPV was rather low. PPI treatment is a common cause of increased CgA concentrations and should always be discontinued before CgA measurement. PIA of CgA could be a way of excluding NET when suspicion is based primarily on elevated CgA.

BackgroundMood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders.MethodsTo clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; non-overlapping N = 609,424).ResultsSeventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder.ConclusionsThe mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum.

Background Blood-brain barrier (BBB) pathology may be associated with mental disorders. The aim of this systematic review and meta-analysis is to identify, evaluate and summarize available evidence on whether potential biomarkers of BBB pathology are altered in patients with schizophrenia spectrum disorders, major depression and bipolar disorder compared to healthy controls. Methods The primary outcome is blood S100B, while secondary outcomes include biomarkers in blood and/or cerebrospinal fluid, i.e. albumin ratio, fibrinogen, immunoglobulin G, glial fibrillary acidic protein, amyloid beta (Aβ), matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases, endothelial glycocalyx constituents, and cell adhesion molecules (CAMs). A systematic search in PubMed, Embase and PsycINFO resulted in 131 eligible studies, of which 93 were included in the meta-analysis. Meta- and subgroup analyses were undertaken using random-effects modelling. The protocol was a priori registered on PROSPERO (CRD42020152721). Results S100B was increased in schizophrenia spectrum disorders (24 studies; 1107 patients; standardized mean difference (SMD) ​= ​0.82; 95% confidence interval (CI) ​= ​0.51 to 1.13; I2 ​= ​90%), major depression (13 studies; 584 patients; SMD ​= ​0.57; 95% CI ​= ​0.31 to 0.83; I2 ​= ​73%) and bipolar disorder (4 studies; 142 patients; SMD ​= ​0.55; 95% CI ​= ​0.16 to 0.94; I2 ​= ​48%). Similarly, numerous secondary outcomes, including albumin ratio, fibrinogen, Aβ, MMPs and CAMs, were altered. Results of the included studies varied considerably, and important confounders were often not accounted for. Conclusions The findings implicate occurrence of BBB pathology in patients with schizophrenia spectrum disorders, major depression and bipolar disorder compared to healthy controls. However, definite conclusions cannot be drawn, mainly because the investigated biomarkers are indirect measures of BBB pathology., Highlights • The blood-brain barrier (BBB) can be studied indirectly through markers in blood and CSF. • Markers of BBB pathology were altered in schizophrenia, depression and bipolar disorder. • The findings implicate occurrence of BBB pathology in patients compared to controls. • BBB pathology is expected to contribute to the pathogenesis of severe mental disorders.

OBJECTIVES: People with severe mental disorders die 10-25years earlier than people in the Western background population, mainly due to lifestyle related diseases, with cardiovascular disease (CVD) being the most frequent cause of death. Major contributors to this excess morbidity and mortality are unhealthy lifestyle factors including tobacco smoking, unhealthy eating habits and lower levels of physical activity. The aim of this study was to investigate the dietary habits and levels of physical activity in people with schizophrenia spectrum disorders and overweight and to compare the results with the current recommendations and with results from the general Danish population.METHODS: We interviewed a sample of 428 people with schizophrenia spectrum disorders and increased waist circumference enrolled in the CHANGE trial using a Food Frequency Questionnaire (FFQ) and a 24h recall interview, a Physical Activity Scale (PAS), scale for assessment of positive and negative symptoms (SAPS and SANS, respectively), Brief Assessment of Cognition in Schizophrenia (BACS) and Global Assessment of Functioning (GAF). We compared with information on dietary intake and physical activity in the general Danish population from the Danish National Survey of Dietary Habits and Physical Activity in 2011-2013 (DANSDA).RESULTS: The CHANGE participants reported a very low energy intake and their distribution of nutrients (i.e. fat, protein and carbohydrates) harmonized with the recommendations from the Danish Health Authorities, and were similar to the latest report on the dietary habits in the Danish general population. However, the intake of saturated fat, sugar and alcohol exceed the recommended amounts and the corresponding intake in the general population. The intake of fiber, vegetables and fruit and fish were insufficient and also less than in the general population. The overall estimated quality of the dietary habits was poor, only 10.7% of the participants had healthy dietary patterns, and the quality was poorer than in the general population. Even with a very liberal definition of the term "homecooked", only 62% of the participants had taken any part in the preparation of their food. The level of physical activity was low and only one fifth of the participants complied with the recommendations of min. 30min daily moderate-to-vigorous activity. Half of the CHANGE participants were smokers, compared to 17% in the general population. Negative symptoms were significantly associated with poorer dietary quality and less physical activity, whereas no such significant associations were found for cognition, positive symptoms or antipsychotic medication.CONCLUSIONS: Even when accounting for some error from recall - and social desirability bias, the findings point in the direction that the average energy intake in obese people with schizophrenia spectrum disorders is not exceeding that of the general population, and that overweight may to some degree be a result of physical inactivity and metabolic adverse effects of antipsychotic medication. The physical activity level is low and the rate of tobacco smoking is high, and our results suggest that negative symptoms play a significant role. Future research should focus on bringing about lifestyle changes in this fragile population in order to reduce the excess risk of CVD and mortality.

BackgroundThe heterogeneity of genetic effects on major depressive disorder (MDD) may be partly attributable to moderation of genetic effects by environment, such as exposure to childhood trauma (CT). Indeed, previous findings in two independent cohorts showed evidence for interaction between polygenic risk scores (PRSs) and CT, albeit in opposing directions. This study aims to meta-analyze MDD-PRS × CT interaction results across these two and other cohorts, while applying more accurate PRSs based on a larger discovery sample.MethodsData were combined from 3024 MDD cases and 2741 control subjects from nine cohorts contributing to the MDD Working Group of the Psychiatric Genomics Consortium. MDD-PRS were based on a discovery sample of ∼110,000 independent individuals. CT was assessed as exposure to sexual or physical abuse during childhood. In a subset of 1957 cases and 2002 control subjects, a more detailed five-domain measure additionally included emotional abuse, physical neglect, and emotional neglect.ResultsMDD was associated with the MDD-PRS (odds ratio [OR] = 1.24, p = 3.6 × 10-5, R2 = 1.18%) and with CT (OR = 2.63, p = 3.5 × 10-18 and OR = 2.62, p = 1.4 ×10-5 for the two- and five-domain measures, respectively). No interaction was found between MDD-PRS and the two-domain and five-domain CT measure (OR = 1.00, p = .89 and OR = 1.05, p = .66).ConclusionsNo meta-analytic evidence for interaction between MDD-PRS and CT was found. This suggests that the previously reported interaction effects, although both statistically significant, can best be interpreted as chance findings. Further research is required, but this study suggests that the genetic heterogeneity of MDD is not attributable to genome-wide moderation of genetic effects by CT.

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened\ud risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified\ud 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and\ud implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved\ud in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression\ud with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were\ud putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry\ud lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression\ud and imply that a continuous measure of risk underlies the clinical phenotype.

Objective A major cause of readmission after transsphenoidal surgery (TSS) is delayed hyponatraemia. The purpose of this study was to identify predictors of hyponatraemia one week post surgery and predictors of 30-day readmissions for hyponatraemia. Design A retrospective cohort study including patients who had TSS performed for pituitary lesions. Method The risk of readmission for hyponatraemia was assessed in consecutive patients between January 2008 and March 2016. The risk of hyponatraemia one week post surgery was assessed in patients admitted for TSS between July 2011 and March 2016. Results Of all included patients, 56/522 (10.7%) were readmitted within 30 days. Hyponatraemia was found in 14/56 (25%) of 30-day readmissions. We did not identify any predictive variable for hyponatraemia on readmission. The number of patients with hyponatraemia on the seventh post-operative day was 26/314 (8.3%). The risk of hyponatraemia one week post surgery was increased by an odds ratio of 2.40 (95% CI: 1.06–5.40) in patients with a tumour abutting the optic chiasm and by an odds ratio of 1.16 (1.04–1.31) per mmol/L decrease in sodium levels on the first post-operative day. Conclusions Hyponatraemia occurred in 25% of readmissions; however, we did not identify any predictive variable for readmission with hyponatraemia. One week post surgery, 8.9% had hyponatraemia. Tumours pressing on the optic chiasm as well as a fall in sodium levels on the first post-operative day were associated with an increased risk of hyponatraemia one week post surgery. We suggest that a day 7 serum sodium

Objectives Recent large cohort studies suggest an association between high plasma prolactin and cardiovascular mortality. The objective of this systematic review was to systematically assess the effect of reducing prolactin with dopamine agonist on established cardiovascular risk factors in patients with prolactinomas. Design Bibliographical search was done until February 2019 searching the following databases: PubMed, EMBASE, WHO and LILAC. Eligible studies had to include participants with verified prolactinomas where metabolic variables were assessed before and after at least 2 weeks treatment with dopamine agonists. Methods Baseline data and outcomes were independently collected by two investigators. The study was registered with PROSPERO (registration number CRD42016046525). Results Fourteen observational studies enrolling 387 participants were included. The pooled standardized mean difference of the primary outcome revealed a reduction of BMI and weight of −0.21 (95% CI −0.37 to −0.05; P = 0.01; I2 = 71%), after treatment. Subgroup analysis suggested that the reduction of weight was primarily driven by studies with high prolactin levels at baseline (P = 0.04). Secondary outcomes suggested a small decrease in waist circumference, a small-to-moderate decrease in triglycerides, fasting glucose levels, HOMA-IR, HbA1c and hsCRP, and a moderate decrease in LDL, total cholesterol and insulin. Conclusion This systematic review suggests a reduction of weight as well as an improved lipid profile and glucose tolerance after treatment with dopamine agonist in patients with prolactinomas. These data are based on low-quality evidence.

Infections and inflammatory processes have been associated with the development of schizophrenia and affective disorders; however, no study has yet systematically reviewed all available studies on cerebrospinal fluid (CSF) immune alterations. We aimed to systematically review the CSF immunological findings in schizophrenia spectrum and affective disorders. We identified all studies investigating CSF inflammatory markers in persons with schizophrenia or affective disorders published prior to March 23, 2017 searching PubMed, CENTRAL, EMBASE, Psychinfo, and LILACS. Literature search, data extraction and bias assessment were performed by two independent reviewers. Meta-analyses with standardized mean difference (SMD) including 95% confidence intervals (CI) were performed on case-healthy control studies. We identified 112 CSF studies published between 1942–2016, and 32 case-healthy control studies could be included in meta-analyses. Studies varied regarding gender distribution, age, disease duration, treatment, investigated biomarkers, and whether recruitment happened consecutively or based on clinical indication. The CSF/serum albumin ratio was increased in schizophrenia (1 study [54 patients]; SMD = 0.71; 95% CI 0.33–1.09) and affective disorders (4 studies [298 patients]; SMD = 0.41; 95% CI 0.23–0.60, I 2 = 0%), compared to healthy controls. Total CSF protein was elevated in both schizophrenia (3 studies [97 patients]; SMD = 0.41; 95% CI 0.15–0.67, I 2 = 0%) and affective disorders (2 studies [53 patients]; SMD = 0.80; 95% CI 0.39–1.21, I 2 = 0%). The IgG ratio was increased in schizophrenia (1 study [54 patients]; SMD = 0.68; 95% CI 0.30–1.06), whereas the IgG Albumin ratio was decreased (1 study [32 patients]; SMD = −0.62; 95% CI −1.13 to −0.12). Interleukin-6 (IL-6) levels (7 studies [230 patients]; SMD = 0.55; 95% CI 0.35–0.76; I 2 = 1%) and IL-8 levels (3 studies [95 patients]; SMD = 0.46; 95% CI 0.17–0.75, I 2 = 0%) were increased in schizophrenia but not significantly increased in affective disorders. Most of the remaining inflammatory markers were not significantly different compared to healthy controls in the meta-analyses. However, in the studies which did not include healthy controls, CSF abnormalities were more common, and two studies found CSF dependent re-diagnosis in 3.2–6%. Current findings suggest that schizophrenia and affective disorders may have CSF abnormalities including signs of blood-brain barrier impairment and inflammation. However, the available evidence does not allow any firm conclusion since all studies showed at least some degree of bias and vastly lacked inclusion of confounding factors. Moreover, only few studies investigated the same parameters with healthy controls and high-quality longitudinal CSF studies are lacking, including impact of psychotropic medications, lifestyle factors and potential benefits of anti-inflammatory treatment in subgroups with CSF inflammation.

Background: Serious mental illness (SMI) reduces life expectancy, primarily due to somatic comorbidity linked to obesity. Meta-analyses have found beneficial effects of lifestyle interventions in people with SMI and recommended their implementation to manage obesity. Objective: The objective of this systematic review was to assess the benefits and harms of individualized lifestyle interventions for weight in people diagnosed with SMI and to explore potential mediators and moderators of the effect. Methods: The protocol was registered at PROSPERO (CRD42016049093). Randomized clinical trials (RCTs) assessing the effect of individualized lifestyle interventions on weight management in people with SMI were included. Primary outcomes were differences in endpoint body mass index (BMI) and the proportion achieving clinically relevant weight loss (≥5%). Secondary outcomes included quality of life, cardiometabolic risk factors, and adverse effects. Results: We included 41 RCTs (n = 4,267). All trials were at high risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions. The experimental interventions reduced the mean difference in BMI by –0.63 kg/m2 (95% confidence interval [CI] = –1.02 to –0.23; p = 0.002; I2 = 70.7%) compared to the control groups. At postintervention follow-up (17 RCTs), the effect size remained similar but was no longer significant (BMI = –0.63 kg/m2; 95% CI = –1.30 to 0.04; p = 0.07; I2 = 48.8%). The risk ratio for losing ≥5% of baseline weight was 1.51 (95% CI = 1.07–2.13; p = 0.02) compared to the control groups. GRADE showed very low or low quality of evidence. Conclusion: There is a statistically significant, but clinically insignificant, mean effect of individualized lifestyle interventions for weight reduction in people with SMI.

ObjectiveDysregulation of the hypothalamic–pituitary–adrenal (HPA) axis has been reported in depression. The aim was to investigate the potential association between depression and seven genes regulating or interfering with the HPA axis, including the gene encoding angiotensin converting enzyme (ACE).MethodsIn total, 78 single nucleotide polymorphisms (SNPs) and one insertion/deletion polymorphism were genotyped. The study included 408 individuals with depression and 289 controls. In a subset of cases, the interaction between genetic variants and stressful life events (SLEs) was investigated.ResultsAfter quality control, 68 genetic variants were left for analyses. Four of nine variants within ACE were nominally associated with depression and a gene-wise association was likewise observed. However, none of the SNPs located within AVP, CRH, CRHR1, CRHR2, FKBP5 or NC3C1 were associated with depression. One nominally significant interaction, most likely due to chance, was identified.ConclusionThe results indicate that ACE could be a potential candidate gene for depression.

Background Many psychological treatments have shown effect on reducing self-harm in adults with borderline personality disorder. There is a need of brief psychotherapeutical treatment alternative for suicide prevention in specialized outpatient clinics. Methods/Design The DiaS trial was designed as a pragmatic single-center, two-armed, parallel-group observer-blinded, randomized clinical superiority trial. The participants had at least two criteria from the borderline personality disorder diagnosis and a recent suicide attempt (within a month). The participants were offered 16 weeks of dialectical behavior therapy (DBT) versus up to 16 weeks of collaborative assessment and management of suicidality (CAMS) treatment. The primary composite outcome was the number of participants with a new self-harm (nonsuicidal self-injury [NSSI] or suicide attempt) at week 28 from baseline. Other exploratory outcomes were: severity of borderline symptoms, depressive symptoms, hopelessness, suicide ideation, and self-esteem. Results At 28 weeks, the number of participants with new self-harm in the DBT group was 21 of 57 (36.8%) versus 12 of 51 (23.5%) in the CAMS treatment (OR: 1.90; 95% CI: 0.80–4.40; P = .14). When assessing the effect of DBT versus CAMS treatment on the individual components of the primary outcome, we observed no significant differences in the number of NSSI (OR: 1.60; 95% CI: 0.70–3.90; P = .31) or number of attempted suicides (OR: 2.24; 95% CI: 0.80–7.50; P = .12). Conclusion In adults with borderline personality traits and disorder and a recent suicide attempt, DBT does not seem superior compared with CAMS for reduction of number of self-harm or suicide attempts. However, further randomized clinical trials may be needed.

Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders., Simone de Jong et al. examine the balance of common and rare risk for psychiatric disorders in a large family with high incidence of Bipolar Disorder and Major Depressive Disorder. They find that increased polygenic risk over generations could be partially due to assortative mating, which may explain the observation of anticipation in mood disorders.

OBJECTIVES: We compared the effectiveness of an intensive smoking cessation intervention among smokers with and without a severe mental disorder (SMD) and identified factors associated with successful quitting. The main hypothesis was that smokers with an SMD would be less likely to stay continuously smoke-free for 6 months.DESIGN: A prospective cohort study.SETTING: In all, 302 smoking cessation clinics in Denmark from municipal clinics, pharmacies, hospitals, midwives, primary care facilities and other private providers who reported data to the national Danish Smoking Cessation Database from 2006 to 2016 participated in this study.PARTICIPANTS: A total of 38 293 patients from the Danish Smoking Cessation Database. Patients with an SMD were identified by linking data to the Danish National Patient Register. Diagnoses of organic mental disorders (F0 chapter) or intellectual disabilities (F7 chapter) were not included. Smokers ≥18 years old who were attending a Gold Standard Programme (GSP) with planned follow-up were included. Smokers not wanting contact after 6 months were excluded.INTERVENTIONS: A comprehensive manual-based smoking cessation intervention comprising five meetings over a 6-week period (the GSP).MAIN OUTCOME MEASURES: Self-reported continuous abstinence at the 6-month follow-up.RESULTS: In all, 69% of the participants participated in the follow-up after 6 months. The overall rate of successful quitting was high but significantly lower in SMD smokers (29% vs 38%; OR 0.74; 95% CI 0.68 to 0.80). Variables associated with successful quitting were compliance (defined as attending ≥75% of the planned meetings), older age and male gender as well as not being disadvantaged, heavy smoking or recommendation of intervention by health professionals.CONCLUSIONS: Only 29% of smokers with an SMD successfully quit smoking which was significantly lower than the 38% of smokers without an SMD. Compliance was the most important predictor for successful quitting.

Background Previous studies indicate that levels of plasma norepinephrine (p-NE) are altered in depressed patients. However, it is unclear whether altered NE metabolism is involved in the pathogenic association between depression and cardiovascular disease. The aim of the present study was, firstly, to investigate if p-NE levels differ between patients with major depression and healthy controls. Secondly, the study sought to assess the associations between p-NE and metabolic variables in all participants. The third and final aim of the study was to assess if the associations between p-NE and metabolic variables are influenced by disease status (depression vs. healthy). Methods 108 patients with major depression and 44 healthy controls were tested for levels of p-NE and metabolic variables that affect cardiovascular risk. Results The median level of p-NE in depressed patients (DSM-IV) was 2636 pg/ml, (IQR 2094–3143) and 2279 pg/ml (IQR 2007–2562) in non-depressed controls (p = 0.013). However, the difference between p-NE levels was non-significant when adjusted for daily smoking (p = 0.138). Significant associations (p ≤ 0.05) were observed between p-NE and p-lipids, mean arterial blood pressure, p-insulin, quantitative insulin sensitivity check index as well as inflammatory markers. Conclusions Elevated levels of p-NE observed in patients with major depression were attributable to daily smoking, rather than to the depressive disorder. Important associations were found between p-NE and metabolic variables that affect cardiovascular risk. This is interesting from a clinical point of view, since affected individuals may benefit from simple and inexpensive treatments that influence sympathetic activity. All associations were independent of disease status.

Chronic psychological stress, the metabolic syndrome (MS) and ischaemic heart disease (IHD) seem closely connected. In this study, we evaluate the association between chronic stress and elements of MS in patients with stable IHD.Cross-sectional cohort study.Three hundred and fifty patients with stable IHD were included. Chronic stress was evaluated by the two questionnaires, Major Depression Inventory (MDI) and the psychological wellbeing index WHO-5, as well as by Pressure Pain Sensitivity (PPS), a physiological measure of hyperalgesia at the sternum known to be associated to elements of the chronic stress syndrome. Elements of MS were evaluated by dual-energy X-ray absorptiometry, body weight, HOMA-IR and blood lipids.Depressive symptoms were associated with a high percentage of body fat (β = 0.179, p = .001), and high level of triglycerides (β = 0.150, p = .007). Low psychological wellbeing was associated with a high percentage of body fat (β = -0.165, p = .002) and low level of HDL cholesterol (β = 0.128, p = .024). Chronic stress measured by PPS was associated with a high percentage body fat (β = 0.327, p .001), low body weight (β = -0.218, p .001) and low HDL-cholesterol (β = -0.137, p = .013). Adjusting for several life style factors did not change these results.In patients with stable IHD, different measures of chronic psychological stress seem associated with a high percentage of body fat and adverse blood lipids independent of several lifestyle factors.

BACKGROUND: Persons with a past episode of self-harm or severe suicidal ideation are at elevated risk of self-harm as well as dying by suicide. It is well established that suicidal ideation fluctuates over time. Previous studies have shown that a personal safety plan can assist in providing support, when a person experiences suicide ideation, and help seeking professional assistance if needed. The aim of the trial is to determine whether a newly developed safety mobile app is more effective in reducing suicide ideation and other symptoms, compared to a safety plan on paper.METHODS/DESIGN: The trial is designed as a two-arm, observer-blinded, parallel-group randomized clinical superiority trial, where participants will either receive: (1) Experimental intervention: the safety plan provided as the app MyPlan, or (2) Treatment as Usual: the safety plan in the original paper format. Based on a power calculation, a total of 546 participants, 273 in each arm will be included. They will be recruited from Danish Suicide Prevention Clinics. Both groups will receive standard psychosocial therapeutic care, up to 8-10 sessions of supportive psychotherapy. Primary outcome will be reduction in suicide ideation after 12 months. Follow-up interviews will be conducted at 3, 6, 9, and 12 months after date of inclusion.DISCUSSION: A safety plan is a mandatory part of the treatment in the Suicide Prevention Clinics in Demark. There are no studies investigating the effectiveness of a safety plan app compared to a safety plan on paper on reducing suicide ideation in patients with suicide ideation and suicidal behavior. The trial will gain new knowledge of whether modern technology can augment the effects of traditional personalized safety planning.TRIAL REGISTRATION: ClinicalTrials.gov, NCT02877316 . Registered on 19 August 2016.

Importance Bereavement after spousal suicide has been linked to mental disorders; however, a comprehensive assessment of the effect of spousal suicide is needed. Objective To determine whether bereavement after spousal suicide was linked to an excessive risk of mental, physical, and social health outcomes when compared with the general population and spouses bereaved by other manners. Design, Setting, and Participants This nationwide, register-based cohort study conducted in Denmark of 6.7 million individuals aged 18 years and older from 1980 to 2014 covered more than 136 million person-years and compared people bereaved by spousal suicide with the general population and people bereaved by other manners of death. Incidence rate ratios were calculated using Poisson regressions while adjusting for sociodemographic characteristics and the presence of mental and physical disorders. Main Outcomes and Measures Mental disorders (any disorder, mood, posttraumatic stress disorder, anxiety, alcohol use disorders, drug use disorders, and self-harm); physical disorders (cancers, diabetes, sleep disorder, cardiovascular diseases, chronic lower respiratory tract diseases, liver cirrhosis, and spinal disc herniation); causes of mortality (all-cause, natural, unintentional, suicide, and homicide); social health outcomes; and health care use. Results The total study population included 3 491 939 men, 4814 of whom were bereaved by spousal suicide, and 3 514 959 women, 10 793 of whom were bereaved by spousal suicide. Spouses bereaved by a partner’s suicide had higher risks of developing mental disorders within 5 years of the loss (men: incidence rate ratio, 1.8; 95% CI, 1.6-2.0; women: incidence rate ratio, 1.7; 95% CI, 1.6-1.8) than the general population. Elevated risks for developing physical disorders, such as cirrhosis and sleep disorders, were also noted as well as the use of more municipal support, sick leave benefits, and disability pension funds than the general population. Compared with spouses bereaved by other manners of death, those bereaved by suicide had higher risks for developing mental disorders (men: incidence rate ratio, 1.7; 95% CI, 1.5-1.9; women: incidence rate ratio, 2.0; 95% CI, 1.9-2.2), suicidal behaviors, mortality, and municipal support. Additionally, a higher level of mental health care use was noted. Conclusions and Relevance Exposure to suicide is stressful and affects the bereaved spouse on a broad range of outcomes. The excess risks of mental, physical, and social health outcomes highlight a need for more support directed toward spouses bereaved by suicide.

Polycystic ovary syndrome (PCOS) is associated with infertility, increased androgen levels and insulin resistance. In adipose tissue, zinc facilitates insulin signaling. Circulating zinc levels are altered in obesity, diabetes, and PCOS, and zinc supplementation can ameliorate metabolic disturbances in PCOS. In adipose tissue, expression of zinc influx transporter ZIP14 varies with body mass index (BMI), clinical markers of metabolic syndrome, and peroxisome proliferator-activated receptor gamma (PPARG). In this study, we investigated expression levels of ZIP14 and PPARG in subcutaneous adipose tissue of 36 PCOS women (17 lean and 19 obese women) compared with 23 healthy controls (7 lean and 16 obese women). Further, expression levels of zinc transporter ZIP9, a recently identified androgen receptor, and zinc efflux transporter ZNT1 were investigated, alongside lipid profile and markers of glucose metabolism (insulin degrading enzyme (IDE), retinol binding protein 4 (RBP4), and glucose transporter 4 (GLUT4)). We find that ZIP14 expression is reduced in obesity and positively correlates with PPARG expression, which is down-regulated with increasing BMI. ZNT1 is up-regulated in obesity, and both ZIP14 and ZNT1 expression significantly correlates with clinical markers of altered glucose metabolism. In addition, RBP4 and GLUT4 associate with obesity, but an association with PCOS as such was present only for PPARG and RBP4. ZIP14 and ZNT1 does not relate to clinical androgen status and ZIP9 is unaffected by all parameters investigated. In conclusion: our findings support the existence of a zinc dyshomeostasis in adipose tissue in metabolic disturbances- including PCOS-related obesity.

ObjectivesTo assess the benefits and harms of exercise in patients with depression.DesignSystematic reviewData sourcesBibliographical databases were searched until 20 June 2017.Eligibility criteria and outcomesEligible trials were randomised clinical trials assessing the effect of exercise in participants diagnosed with depression. Primary outcomes were depression severity, lack of remission and serious adverse events (eg, suicide) assessed at the end of the intervention. Secondary outcomes were quality of life and adverse events such as injuries, as well as assessment of depression severity and lack of remission during follow-up after the intervention.ResultsThirty-five trials enrolling 2498 participants were included. The effect of exercise versus control on depression severity was −0.66 standardised mean difference (SMD) (95% CI −0.86 to −0.46; pConclusionsTrials with less risk of bias suggested no antidepressant effects of exercise and there were no significant effects of exercise on quality of life, depression severity or lack of remission during follow-up. Data for serious adverse events and adverse events were scarce not allowing conclusions for these outcomes.Systematic review registrationThe protocol was published in the journalSystematic Reviews: 2015; 4:40.

Hyperprolactinemia has been suspected to increase mortality risk, but the available data are conflicting. The objective of this study was to estimate the association between hyperprolactinemia and all-cause and cardiovascular mortality among patients referred for assessment of prolactin. For this study, adults with no prio pituitary disease who underwent prolactin assessment at 3 university Hospitals in Denmark between 2001 and 2011 were included in a retrospective cohort study. A total of 3 633 patients with a median follow-up time of 5.3 years (IQR 2.7–5.7) were included. Mean (SD) age 39.7 (15.5) years and 78% female. 373/3 633 (10.3%) had hyperprolactinemia and during follow-up 330/3 633 (9.1%) patients died of any cause, and 113/3 633 (3.1%) patients died of cardiovascular causes. In males, hyperprolactinemia was associated with age-adjusted incidence rate ratio (IRR) of 1.86 for all-cause mortality (95% CI 1.22–2.82) and 2.55 (95% CI 1.43–4.55) for cardiovascular mortality. The IRR for all-cause mortality was reduced to 1.37 (0.90–2.08) when adjusted for the use of antipsychotic medication. The association between hyperprolactinemia and cardiovascular mortality remained after adjusting for confounders, for example, chronic renal failure, diabetes, and antipsychotic medication. In females, hyperprolactinemia was not associated with all-cause mortality (IRR 1.45; CI 0.86–2.47) or cardiovascular mortality (IRR 0.58; CI 0.14–2.39). In conclusion, hyperprolactinemia was associated with increased cardiovascular mortality in male patients. This association was not found in female patients. Focus on increased cardiovascular risk in males with hyperprolactinemia is warranted.

Henriette Thisted Horsdal,1,2 Michael Eriksen Benros,2,3 Ole Köhler-Forsberg,2–4 Jesper Krogh,3 Christiane Gasse1,2,5 1National Centre for Register-based Research, Department of Economics and Business Economics, Aarhus BSS, Aarhus University, Aarhus, 2The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, 3Faculty of Health Sciences, Mental Health Centre Copenhagen, University of Copenhagen, Copenhagen, 4Psychosis Research Unit, Aarhus University Hospital, Risskov, 5Centre for Integrated Register-Based Research, Aarhus University, Aarhus, Denmark Objective: Schizophrenia and/or antipsychotic drug use are associated with metabolic abnormalities; however, knowledge regarding metabolic status and physician’s monitoring of metabolic status at first schizophrenia diagnosis is sparse. We assessed the prevalence of monitoring for metabolic blood abnormalities and characterized the metabolic profiles in people with a first-time schizophrenia diagnosis. Methods: This is a population-based cross-sectional study including all adults born in Denmark after January 1, 1955, with their first schizophrenia diagnosis between 2000 and 2012 in the Central Denmark Region. Information on metabolic parameters was obtained from a clinical laboratory information system. Associations were calculated using Wilcoxon rank-sum tests, chi-square tests, logistic regression, and Spearman’s correlation coefficients. Results: A total of 2,452 people with a first-time schizophrenia diagnosis were identified, of whom 1,040 (42.4%) were monitored for metabolic abnormalities. Among those monitored, 58.4% had an abnormal lipid profile and 13.8% had an abnormal glucose profile. People who had previously filled prescription(s) for antipsychotic drugs were more likely to present an abnormal lipid measure (65.7% vs 46.8%, P

Background Physical activity is inversely associated with the risk of cardiovascular disease, diabetes and all-cause mortality. Patients with depression are less likely to be physically active, and thus more prone to developing these diseases. The aim of this study was to identify patient and study characteristics associated with adherence to exercise interventions. Method We pooled data from patients allocated to active exercise interventions from two previously conducted exercise trials ( n = 166) offering two or three weekly sessions. We divided the patients into a high attendance or a low attendance group. We then compared patient characteristics, distance to training facilities, depression, anxiety, and satisfaction with the offered intervention between the two groups. Results High attendance was positively associated with age ( p = 0.05) and satisfaction with the intervention ( p p = 0.008) and improvement in depression ( p = 0.04). Median attendance did not differ between the two trials offering two or three sessions per week ( p = 0.44). Conclusion Severity of depression or anxiety in mild to moderate depression did not predict attendance, but high attendance was associated with higher age and satisfaction with the intervention. These findings suggest that motivational focus on younger participants should be encouraged and ways to improve satisfaction with the intervention should be considered.

Background Infections and inflammatory processes have been associated with the development of schizophrenia and affective disorders; however, no study has yet synthesized all the available data on cerebrospinal fluid (CSF) immune-alterations. We conducted the first systematic review of the immunological findings from CSF studies among patients with schizophrenia or affective disorders. Methods All studies investigating CSF inflammatory markers in persons with schizophrenia or affective disorders published prior to March 23, 2017 were identified searching PubMed, CENTRAL, EMBASE, Psychinfo, and LILACS. The literature search, data extraction and assessment of risk of bias were performed by two independent reviewers. Meta-analyses with standardized mean difference (SMD) including 95% confidence intervals (CI) were performed on studies including healthy controls. Results We identified 112 CSF studies published between 1942–2016, of which 32 were included in meta-analyses; however, only few studies investigated identical biomarkers. The CSF/serum albumin ratio was increased in both schizophrenia (54 patients; SMD=0.62; 95%CI=0.24–1.00) and affective disorders (302 patients; SMD=0.43; 95%CI=0.25–0.61, I2=0%), compared to healthy controls. Total CSF protein was elevated in both schizophrenia (97 patients; SMD=0.38; 95%CI=0.12–0.65, I2=0%) and affective disorders (53 patients; SMD=0.77; 95%CI=0.36–1.18, I2=0%). The IgG ratio was increased in schizophrenia (54 patients; SMD=0.60; 95%CI=0.23–0.98), whereas the IgG Albumin ratio was decreased (32 patients; SMD= -0.62; 95%CI= -1.13 to -0.12). Interleukin-8 (IL-8) (95 patients; SMD=0.46; 95%CI=0.17–0.75, I2=0%) and IL-6 levels (230 patients; SMD=0.38; 95%CI=0.02–0.74; I2=64%) were increased among individuals with schizophrenia but not significantly increased in affective disorders. None of the remaining inflammatory markers were significantly different compared to healthy controls in the meta-analyses. However, in the studies which did not include healthy controls, CSF abnormalities were more common, and CSF dependent re-diagnosis occurred in 3.2–6% in the two studies investigating this. Discussion Our findings suggests that schizophrenia spectrum and affective disorders are associated with CSF abnormalities including signs of blood-brain barrier impairment and inflammation, supporting a role of the immune system in mental disorders. However, only few studies investigated the same parameters with healthy controls and high quality longitudinal CSF studies are lacking, including impact of psychotropic medications and potential benefits of anti-inflammatory treatment in subgroups with abnormal CSF inflammatory markers

Background High vasopressin levels and a correlation between vasopressin and cortisol has been observed in patients with depression. The aim was to assess copeptin, the c-terminal of provasopressin, and the association between cortisol, adrenocorticotropic hormone (ACTH) and copeptin in patients with depression. Secondly, to examine the copeptin response to acute exercise and aerobic training. Methods Copeptin, ACTH, and cortisol were measured in 111 patients with depression and 57 controls at rest. Copeptin was also measured during exercise. The depressed patients were subsequently randomized to an aerobic training intervention or an exercise control intervention. Results The plasma level of copeptin in depressed subjects was 5.14 pg/ml (IQR 3.4–8.4) and 4.82 pg/ml (IQR 2.8–7.5) in healthy controls ( p =.66). The association between copeptin and cortisol was.02 (95% CI –.44 to.48; p =.93) and the association between copeptin and ACTH was –.06 (95% CI –.17 to.05; p =.27). All associations were independent of depression status ( p =.15). Aerobic exercise training did not influence copeptin levels at rest ( p =.09) or the response to acute exercise ( p =.574). Copeptin decreased at rest in response to aerobic training in participants with high compliance to the exercise intervention ( p =.04). Limitations We did not measure plasma osmolality, which is a possible confounder in this study. Conclusions Copeptin levels are not elevated or associated to ACTH or cortisol in depressed patients. Aerobic exercise training decreased copeptin levels in high attenders only. This study does not support a role of copeptin or vasopressin in depression.

Background: Depression has been associated with increased oxidative stress and hypothesized to accelerate aging. Nucleic acid damage from oxidation is a critical part of the aging process, and a suggested early event in age-related somatic morbidities that are also prevalent in depression, such as dementia and type 2 diabetes. We hypothesized that increased severity of depression is associated with increased systemic oxidatively generated DNA and RNA damage, and that this increase is attenuated by an effective antidepressant treatment. Methods: The urinary excretion of markers of systemic oxidatively generated DNA and RNA damage, 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), respectively, were determined in healthy controls (N ¼ 28), moderately depressed, non-medicated patients (N ¼ 26) and severely depressed patients eligible for electroconvulsive therapy (ECT) (N¼ 29). In the severely depressed patient group, samples were also obtained 1 week after the completion of ECT. Results: Systemic RNA damage from oxidation, as measured by 8-oxoGuo excretion, was higher with increasing severity of depression (controlsomoderately depressedo severely depressed) (P for trend ¼ 0.004). The 8-oxoGuo excretion was further increased after clinically effective ECT compared with pre-ECT values (P¼0.006). There were no differences in 8-oxodG excretion between the groups or pre- vs. post-ECT. Limitations: Small sample size and the inclusion of both unipolar and bipolar patients in the severely depressed group. Conclusions: Severe depression is associated with increased systemic oxidatively generated RNA damage, which may be an additional factor underlying the somatic morbidity and neurodegenerative features associated with depression. Due to the lack of normalization by clinically effective ECT, the phenomenon does not appear to be causally linked to the depressive state per se.

Life expectancy in patients with schizophrenia is reduced by 20 years for men and 15 years for women compared to the general population. About 60% of the excess mortality is due to physical illnesses, with cardiovascular disease being dominant. CHANGE was a randomized, parallel-group, superiority, multi-centre trial with blinded outcome assessment, testing the efficacy of an intervention aimed to improve cardiovascular risk profile and hereby potentially reduce mortality. A total of 428 patients with schizophrenia spectrum disorders and abdominal obesity were recruited and centrally randomized 1:1:1 to 12 months of lifestyle coaching plus care coordination plus treatment as usual (N=138), or care coordination plus treatment as usual (N=142), or treatment as usual alone (N=148). The primary outcome was 10-year risk of cardiovascular disease assessed post-treatment and standardized to age 60. At follow-up, the mean 10-year risk of cardiovascular disease was 8.4 ± 6.7% in the group receiving lifestyle coaching, 8.5 ± 7.5% in the care coordination group, and 8.0 ± 6.5% in the treatment as usual group (p=0.41). We found no intervention effects for any secondary or exploratory outcomes, including cardiorespiratory fitness, physical activity, weight, diet and smoking. In conclusion, the CHANGE trial did not support superiority of individual lifestyle coaching or care coordination compared to treatment as usual in reducing cardiovascular risk in patients with schizophrenia spectrum disorders and abdominal obesity.

Patients with depression display neurobiological changes of the hypothalamic-pituitary axis as well as cognitive disturbances.To assess any association between hypothalamus-pituitary-adrenal (HPA) axis reactivity and memory-related cognitive functions.Depressed outpatients (n = 83, ICD-10) were group-matched to healthy controls (n = 33), and tested on a number of cognitive domains. Salivary samples were collected at awakening, 30 min later and at 22:00 h. At 23:00 h, the participants ingested 1.0 mg of dexamethasone, and three saliva samples were collected the following day at the same times.Patients and controls did not differ on any memory-related cognitive skills. After dexamethasone the cortisol level was 1.7 nmol/l higher (95% CI 0.0-2.8, P = 0.05) in depressed patients compared with controls. In the control group, but not in the patients, a positive association between post-DST cortisol and Rey's Complex figure test (1.3; 95% CI 0.3-3.6; P = 0.02) was found. We found no significant associations between other memory functions and cortisol measures.Contrary to our hypothesis, we found a positive association between cortisol levels after dexamethasone and visuo-spatial memory primarily driven by the healthy controls. Otherwise, no association were found between HPA axis reactivity and memory-related cognitive function.

Objective To assess the effectiveness of exercise in adults with clinical depression. Data sources The databases CINAHL, Embase, Cochrane Database of Systematic reviews, Cochrane Controlled Trials Register, MEDLINE, and PsycINFO were searched (1806-2008) using medical subject headings (MeSH) and text word terms depression, depressive disorder and exercise, aerobic, non-aerobic, physical activity, physical fitness, walk*, jog*, run*, bicycling, swim*, strength, and resistance. Study selection Randomized trials including adults with clinical depression according to any diagnostic system were included. Data extraction Two investigators evaluated trials using a prepiloted structured form. Data synthesis Thirteen trials were identified that fulfilled the inclusion criteria. Eight had adequate allocation concealment, 6 had a blinded outcome, and 5 used intention-to-treat analyses. The pooled standardized mean difference (SMD) calculated using a random-effects model was -0.40 (95% CI, -0.66 to -0.14), with evidence of heterogeneity between trials (I(2) = 57.2%, P = .005). There was an inverse association between duration of intervention and the magnitude of the association of exercise with depression (P = .002). No other characteristics were related to between-study heterogeneity. Pooled analysis of 5 trials with long-term follow-up (ie, that examined outcomes beyond the end of the intervention) suggested no long-term benefit (SMD, -0.01; 95% CI, -0.28 to 0.26), with no strong evidence of heterogeneity in this pooled analysis (I(2) = 23.4%, P = .27). There was no strong statistical evidence for small study bias (P > .27). Only 3 studies were assessed as high quality (adequately concealed random allocation, blinded outcome assessment, and intention-to-treat analysis). When we pooled results from these, the estimated beneficial effect of exercise was more modest (SMD, -0.19; 95% CI, -0.70 to 0.31) than the pooled result for all 13 studies, with no strong evidence of benefit. Conclusions Our results suggest a short-term effect of exercise on depression: on average, depression scores 0.4 of a standard deviation lower in clinically depressed patients randomly assigned to an exercise intervention at the end of that intervention compared to those randomly assigned to a none exercise group. There is little evidence of a long-term beneficial effect of exercise in patients with clinical depression.

Background: A blunted growth hormone and prolactin response to pharmacological stress test have previously been found in depressed patients, as well as an increased cortisol response to psychosocial stress. This study investigated these hormones in response to acute exercise using an incremental bicycle test. Method: A cross-sectional comparison of cortisol, growth hormone, and prolactin in depressed (n = 137) and healthy (n = 44) subjects during rest and in response to an incremental bicycle test. Secondly, we tested the depressed patients again after a 4-month randomized naturalistic exercise intervention. Results: Resting plasma levels of growth hormone (GH), cortisol, or prolactin (PRL) did not differ between depressed and healthy subjects (all p-values > .12). In response to an incremental bicycle test the GH (p = .02) and cortisol (p = .05) response in depressed was different compared to healthy controls. The effect of acute exercise stress on PRL (p = .56) did not differ between depressed and healthy subjects. Apart from a decrease in CH response in the strength-training group (p = .03) the pragmatic exercise intervention did not affect resting hormonal levels, or the response to acute exercise. Conclusions: Patients with mild to moderate depression had a different growth hormone and cortisol response to acute exercise stress compared to healthy controls. Strength training was able to reduce the growth hormone response to acute exercise stress in this patient population. Studies with more rigorous inclusion criteria and higher exercise frequencies are needed to evaluate and confirm the possible effect of exercise in depressed subjects. (C) 2010 Elsevier B.V. All rights reserved.

Objective To assess the benefit and harm of exercise training in adults with clinical depression. Method The DEMO trial is a randomized pragmatic trial for patients with unipolar depression conducted from January 2005 through July 2007. Patients were referred from general practitioners or psychiatrists and were eligible if they fulfilled the International Classification of Diseases, Tenth Revision, criteria for unipolar depression and were aged between 18 and 55 years. Patients (N = 165) were allocated to supervised strength, aerobic, or relaxation training during a 4-month period. The primary outcome measure was the 17-item Hamilton Rating Scale for Depression (HAM-D(17)), the secondary outcome measure was the percentage of days absent from work during the last 10 working days, and the tertiary outcome measure was effect on cognitive abilities. Results At 4 months, the strength measured by 1 repetition maximum for chest press increased by a mean (95% CI) of 4.0 kg (0.8 to 7.2; p = .014) in the strength training group versus the relaxation group, and maximal oxygen uptake increased by 2.7 mL/kg/min (1.2 to 4.3; p = .001) in the aerobic group versus the relaxation group. At 4 months, the mean change in HAM-D(17) score was -1.3 (-3.7 to 1.2; p = .3) and 0.4 (-2.0 to 2.9; p = .3) for the strength and aerobic groups versus the relaxation group. At 12 months, the mean differences in HAM-D(17) score were -0.2 (-2.7 to 2.3; p = .8) and 0.6 (-1.9 to 3.1; p = .6) for the strength and aerobic groups versus the relaxation group. At 12 months, the mean differences in absence from work were -12.1% (-21.1% to -3.1%; p = .009) and -2.7% (-11.7% to 6.2%; p = .5) for the strength and aerobic groups versus the relaxation group. No statistically significant effect on cognitive abilities was found. Conclusion Our findings do not support a biologically mediated effect of exercise on symptom severity in depressed patients, but they do support a beneficial effect of strength training on work capacity. Trial registration (ClinicalTrials.gov) Identifier: NCT00103415.

Accumulating evidence supports an association between depression and inflammatory processes, a connection that seems to be bidirectional. Clinical trials have indicated antidepressant treatment effects for anti-inflammatory agents, both as add-on treatment and as monotherapy. In particular, nonsteroidal anti-inflammatory drugs (NSAIDs) and cytokine-inhibitors have shown antidepressant treatment effects compared to placebo, but also statins, poly-unsaturated fatty acids, pioglitazone, minocycline, modafinil, and corticosteroids may yield antidepressant treatment effects. However, the complexity of the inflammatory cascade, limited clinical evidence, and the risk for side effects stress cautiousness before clinical application. Thus, despite proof-of-concept studies of anti-inflammatory treatment effects in depression, important challenges remain to be investigated. Within this paper, we review the association between inflammation and depression together with the current evidence on use of anti-inflammatory treatment in depression. Based on this, we address the questions and challenges that seem most important and relevant to future studies, such as timing, most effective treatment lengths and identification of subgroups of patients potentially responding better to different anti-inflammatory treatment regimens.