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Objective: To estimate the proportion of patients with persistent normoprolactinaemia following dopamine agonist (DA) withdrawal and to identify predictors of successful withdrawal in patients with hyperprolactinaemia. Design, patients, and measurements: A systematic review of observational eligible studies were identified by searching PubMed and Embase. The primary outcome was the proportion of patients with normoprolactinaemia after cessation of DA treatment. Secondary outcome included the proportion of patients with normoprolactinaemia after DA withdrawal using individual patient data. Risk of bias was assessed by using Newcastle-Ottawa Scale. Pooled proportions were estimated using a random effects model in case I2 ≤ 75% or by reporting range of effects if I2 > 75%. Results: Thirty-two observational studies enroling 1563 patients were included. The proportion of patients with persistent normoprolactinaemia ranged from 0% to 75% (I2 = 84%). Heterogeneity was partly explained by age with more successful withdrawal in patients of higher age. Individual patient data analyses suggested that the proportion of patients with persistent normoprolactinaemia 6 months after DA withdrawal with a low maintenance dose and full regression of the prolactinoma was 87.7% (95% confidence interval [CI] = 60.7–97.1; I2 = 0%) and 58.4% (95% CI = 23.8–86.3; I2 = 75%) for microadenomas and macroadenomas, respectively. Conclusions: The proportion of patients with persistent normoprolactinaemia following DA withdrawal treatment varied greatly, partly explained by the mean age of participants of the individual studies. Individual patient data analysis suggested that successful withdrawal was likely in patients with full regression of prolactinomas using a low maintenance dose before cessation.

Introduction: Transsphenoidal surgery is the current treatment for mass reduction in patients with non-functional pituitary adenomas (NFPAs). The surgical procedure may deteriorate or recover pituitary endocrine function. The aim of this study was to systematically assess the benefits and harms of transsphenoidal surgery on pituitary endocrine function in patients with NFPAs. Methods: This systematic review and meta-analysis was registered with PROSPERO (registration No. CRD42020210853). We searched Pubmed and EMBASE for studies reporting on pituitary function before and after transsphenoidal surgery in patients with NFPAs having a minimum follow-up of 1 month. The prespecified primary outcomes were the proportions of patients with improved or deteriorated pituitary function after surgery reported as weighted mean using random effects meta-analysis or in case of considerable heterogeneity, i.e., I2 ≥ 75%, as a range of reported proportions. Subgroup analyses were planned for the primary outcomes on study level. Results: Of the 6,597 identified records, 24 studies enrolling 3,816 participants were eligible for assessment. Twenty-three studies were judged to have serious or critical risk of bias. The range of proportions of patients with recovery of at least one pituitary axis was between 10.2% and 97.7% (I2 = 93%), while the range of proportions of patients experiencing loss of at least one axis after pituitary surgery was between 0.0% and 36.6% (I2 = 91%). None of the a priori planned subgroup analyses explained the observed heterogeneity associated with deterioration of pituitary function after surgery, and the proportion of patients may be underestimated due to publication bias. Conclusions: The current systematic review finds that the endocrine effect of pituitary surgery is unclear both in terms of the chance of recovery and in terms of the risk of pituitary failure and hypopituitarism should be considered only a relative indication for surgery. However, the range of effects does include potentially clinically relevant rates of pituitary recovery calling for more systematic collection of data in future studies.

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.

Adrenalectomy for primary aldosteronism (PA) has been associated with decreased kidney function after surgery. It has been proposed that elimination of excess aldosterone unmasks an underlying failure of the kidney function. Contralateral suppression (CLS) is considered a marker of aldosterone excess and disease severity, and the purpose of this study was to assess the hypothesis that CLS would predict change in kidney function after adrenalectomy in patients with PA.Patients with PA referred for adrenal venous sampling (AVS) between May 2011 and August 2021 and who were subsequently offered surgical or medical treatment were eligible for the current study.A total of 138 patients were included and after AVS 85/138 (61.6%) underwent adrenalectomy while 53/138 (38.4%) were treated with MR-antagonists. In surgically treated patients the estimated glomerular filtration rate (eGFR) was reduced by 11.5 (SD: 18.5) compared to a reduction of 5.9 (SD: 11.5) in medically treated patients (p = .04). Among surgically treated patients, 59/85 (69.4%) were classified as having CLS. After adrenalectomy, patients with CLS had a mean reduction in eGFR of 17.5 (SD: 17.6) compared to an increase of 1.8 (SD: 12.8) in patients without CLS (p .001). The association between CLS and change in kidney function remained unchanged in multivariate analysis. Post-surgery, 16/59 (27.1%) patients with CLS developed hyperkalemia compared to 2/26 (7.7%) in patients without CLS (p = .04).This retrospective study found that CLS was a strong and independent predictor of a marked reduction of eGFR and an increased risk of hyperkalemia after adrenalectomy in patients with PA.

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.

Background: Non-suicidal self-injury (NSSI) is a growing healthcare problem. Individuals with NSSI have an increased risk of suicidality. Because of stigma, they may self-injure in secret, which means they often seek help when events have escalated to suicidal ideation or a mental disorder. Previous studies have shown that interventions delivered via mobile phone applications have the potential to reduce self-injury. This protocol outlines a trial, which examines whether the Zero Self Harm-intervention, which is based on an app created for people with NSSI, can reduce the number of NSSI-episodes, suicide ideation, and depressive symptoms. Methods: The trial will be conducted as a 6-month 2-arm, parallel-group, multicentre, pragmatic, randomized clinical superiority trial. The intervention group will receive the app and instructions on how to use it, while the control group will be allocated to a waitlist and allowed to download the app after 6 months. Participants will be asked to complete questionnaires at 3- and 6 months after date of inclusion and the primary outcome is the number of NSSI-episodes during the last month, as measured at the 3 months follow-up with the Deliberate Self-Harm Inventory. A total of 280 participants, 140 in each arm, will be included.Discussion: This trial will assess the effectiveness of the Zero Self Harm-intervention to reduce the number of NSSI episodes. If effective, the app will have the potential to support to large group of people with NSSI. NSSI is stigmatised and often done in secret. Being both discreet and anonymous, the app might be an appealing option for support. In addition, people with current or former NSSI were involved in the development of the app. The app was developed with a focus on minimizing harm, not to end NSSI, which might also make the app appealing for a broader group of users.Trial registration: ClinicalTrials.gov, NCT04463654. Registered on 7 June 2020

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.

Mutations in hepatocyte nuclear factor 1-alpha (HNF1A) cause HNF1A-diabetes (or maturity-onset diabetes of the young type 3 (MODY3)) . Treatment of HNF1A-diabetes is primarily based on sulphonylureas (SU) and secondarily insulins, glucagon-like peptide 1 receptor agonists (GLP1-RA) and dipeptidyl peptidase-4 inhibitors (DPP4i) . Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are effective glucose-lowering agents, cause body weight loss and protect from chronic kidney disease, heart failure and major adverse cardiovascular events. The utility of SGLT2i in patients with HNF1A-diabetes is unknown. Here, we describe a case series of five patients with HNF1A-diabetes treated with SGLT2i. Patient characteristics (median [range]) : age: 52 [35; 68] years; men/women: n=4/1; diabetes duration: 23 [9; 55] years; age at diabetes onset: 18 [13; 44] years; HbA1c: 6.9 [6.0; 7.4]% (52 [42; 57] mmol/mol) ; body weight: 92.3 [65.5; 95.1] kg; BMI: 25.6 [23.8; 29.4] kg/m2. At baseline, patients were treated with SU (n=5) , insulin (n=3; total daily dose: 15 [6; 25] IE divided into 1-4 injections/day) , DPP-4i (n=3) , GLP1-RA (n=2) , metformin (n=1) . All patients were started on empagliflozin mg QD. Follow-up was 1.5 [0.7; 1.8] years (total 6.2 patient years) . After three to six months of SGLT2i therapy, HbA1c was 6.1 [5.5; 7.5]% (43 [37; 59] mmol/mol) and had decreased in four patients (HbA1c change: -0.5 [-1.3; 0.7]% (-5 [-14; 8] mmol/mol)) , while body weight had decreased in all patients (change: -3.4 [-5.9; -1.5] kg) . During SGLT2i treatment, insulin was fully ceased in two patients and insulin dose was reduced from 15 IE/day to 3 IE/day in one patient. No serious adverse events were reported. Our data suggest that SGLT2i is safe, have glucose-lowering effects and is well-tolerated in HNF1A-diabetes, but randomized controlled trials are needed. Disclosure H.Maagensen: None. S.Haedersdal: None. J.Krogh: None. T.Hansen: None. F.K.Knop: Advisory Panel; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi, ShouTi, Zucara Therapeutics, Consultant; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Pharmacosmos A/S, Sanofi, ShouTi, Zealand Pharma A/S, Zucara Therapeutics, Research Support; AstraZeneca, Novo Nordisk, Sanofi, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Stock/Shareholder; Antag Therapeutics. T.Vilsbøll: Consultant; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk, Sun Pharmaceutical Industries Ltd.

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

Objective: Primary aldosteronism (PA) is the most common cause of endocrine hypertension and adrenalectomy is the firstline treatment for unilateral PA. Suppression of aldosterone secretion of the nondominant adrenal gland at adrenal venous sampling (AVS), that is, contralateral suppression (CLS) has been suggested as a marker of disease severity. However, whether factors such as CLS, age, gender or comorbidities are associated with remission after surgery is controversial. The objective of this study is to investigate the prognostic value of CLS, age, gender, aldosterone-to-renin ratio, antihypertensives and comorbidities for clinical and biochemical remission following unilateral adrenalectomy in patients with PA. Design and patients: A retrospective study of patients with PA referred for AVS at Rigshospitalet from May 2011 to September 2020, who subsequently underwent adrenalectomy. Clinical remission was defined according to the PA surgical outcome criteria, whereas complete biochemical remission was defined as normalization of hypokalaemia without potassium substitution. Results: Eighty-four patients were available for analysis of primary outcome. Among patients with CLS, 28/58 (48.3%) obtained complete clinical remission after surgery compared with 10/26 (38.5%) without CLS (p =.40). Complete biochemical remission was obtained in 55/58 (94.8%) of patients with CLS compared with 25/28 (89.3%) without CLS (p =.44). Female gender and lower number of antihypertensives at baseline were associated with higher odds for complete clinical remission, whereas none of the investigated variables were associated with biochemical remission. Conclusion: CLS was not significantly associated with complete clinical or biochemical remission in this cohort. Our results confirmed that female gender and lower number of antihypertensives were predictors of clinical remission.

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.

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 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.

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.