Differences in the gut microbiome of young adults with schizophrenia spectrum disorder: using machine learning to distinguish cases from controls.

While an association between the gut microbiome and schizophrenia spectrum disorders (SSD) has been suggested, the existing evidence is still inconclusive. To this end, we analyzed bacteria and bacterial genes in feces from 52 young adult SSD patients and 52 controls using fecal shotgun metagenomic sequencing. Compared to controls, young SSD patients were found to have significantly lower α-diversity and different ß-diversity both regarding bacterial species (i.e., taxonomic diversity) and bacterial genes (i.e., functional diversity). Furthermore, the α-diversity measures 'Pielou's evenness' and 'Shannon' were significantly higher for both bacterial species, bacterial genes encoding enzymes and gut brain modules in young SSD patients on antipsychotic treatment (young SSD not on antipsychotics=9 patients, young SSD on antipsychotics=43 patients). We also applied machine learning classifiers to distinguish between young SSD patients and healthy controls based on their gut microbiome. Results showed that taxonomic and functional data classified young SSD individuals with an accuracy of ≥ 70% and with an area under the receiver operating characteristic curve (AUROC) of ≥ 0.75. Differential abundance analysis on the most important features in the classifier models revealed that most of the species with higher abundance in young SSD patients had their natural habitat in the oral cavity. In addition, many of the modules with higher abundance in young SSD patients were amino acid biosynthesis modules. Moreover, the abundances of gut-brain modules of butyrate synthesis and acetate degradation were lower in the SSD patients compared to controls. Collectively, our findings continue to support the presence of gut microbiome alterations in SSD and provide support for the use of machine learning algorithms to distinguish patients from controls based on gut microbiome profiles.

Efficacy of a synbiotic in the management of adults with Attention-Deficit and Hyperactivity Disorder and/or Borderline Personality Disorder and high levels of irritability: Results from a multicenter, randomized, placebo-controlled, "basket" trial.

Irritability worsens prognosis and increases mortality in individuals with Attention-Deficit and Hyperactivity Disorder (ADHD) and/or Borderline Personality Disorder (BPD). However, treatment options are still insufficient. The aim of this randomized, double blind, placebo-controlled study was to investigate the superiority of a synbiotic over placebo in the management of adults with ADHD and/or BPD and high levels of irritability. The study was conducted between February 2019 and October 2020 at three European clinical centers located in Hungary, Spain and Germany. Included were patients aged 18-65 years old diagnosed with ADHD and/or BPD and high levels of irritability (i.e., an Affectivity Reactivity Index (ARI-S) ≥ 5, plus a Clinical Global Impression-Severity Scale (CGI-S) score ≥ 4). Subjects were randomized 1(synbiotic):1(placebo); the agent was administered each day, for 10 consecutive weeks. The primary outcome measure was end-of-treatment response (i.e., a reduction ≥ 30 % in the ARI-S total score compared to baseline, plus a Clinical Global Impression-Improvement (CGI-I) total score of < 3 (very much, or much improved) at week 10). Between-treatment differences in secondary outcomes, as well as safety were also investigated. Of the 231 included participants, 180 (90:90) were randomized and included in the intention-to-treat-analyses. Of these, 117 (65 %) were females, the mean age was 38 years, ADHD was diagnosed in 113 (63 %), BPD in 44 (24 %), both in 23 (13 %). The synbiotic was well tolerated. At week 10, patients allocated to the synbiotic experienced a significantly higher response rate compared to those allocated to placebo (OR: 0.2, 95 % CI:0.1 to 0.7; P = 0.01). These findings suggest that that (add-on) treatment with a synbiotic may be associated with a clinically meaningful improvement in irritability in, at least, a subgroup of adults with ADHD and/or BPD. A superiority of the synbiotic over placebo in the management of emotional dysregulation (-3.6, 95 % CI:-6.8 to -0.3; P = 0.03), emotional symptoms (-0.6, 95 % CI:-1.2 to -0.05; P = 0.03), inattention (-1.8, 95 % CI: -3.2 to -0.4; P = 0.01), functioning (-2.7, 95 % CI: -5.2 to -0.2; P = 0.03) and perceived stress levels (-0.6, 95 % CI: -1.2 to -0.05; P = 0.03) was also suggested. Higher baseline RANK-L protein levels were associated with a significantly lower response rate, but only in the synbiotic group (OR: 0.1, 95 % CI: -4.3 to - 0.3, P = 0.02). In the placebo group, higher IL-17A levels at baseline were significantly associated with a higher improvement in in particular, emotional dysregulation (P = 0.04), opening a door for new (targeted) drug intervention. However, larger prospective studies are warranted to confirm the findings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03495375.

Association of preterm birth and birth size status with neurodevelopmental and psychiatric disorders in spontaneous births.

Preterm birth (PTB) or small birth size are risk factors for certain neurodevelopmental disorders. The magnitude of these associations in spontaneous births, and of associations for combined PTB and birth size status on neurodevelopmental and psychiatric disorders is unexplored. We investigated whether PTB and small/large for gestational age (SGA/LGA), separately or combined, in spontaneous births, are associated with a wide spectrum of neurodevelopmental and psychiatric disorders. In this population-based registry cohort study, all singleton spontaneous births in Finland from 1996 to 2014 were followed until 2018 (n = 819 764). We show that PTB across gestational ages, and SGA, were associated with higher risks for anxiety disorders, intellectual disabilities, specific developmental disorders (SDD), autism spectrum disorders (ASD), attention-deficit/hyperactivity disorders (ADHD) and other emotional and behavioural disorders (F98). Most of these associations were not attributed to familial factors. Larger effect sizes were observed with lower gestational ages. Extremely PTB was associated at highest risks with intellectual disabilities (HR, 10.70 [95%CI, 8.69-13.17]) and SDD (HR, 8.91 [95%CI, 8.18-9.71]). Moreover, very preterm birth combined with SGA was associated with a higher risk for SDD (HR, 7.55 [95%CI, 6.61-8.62]) than that of very preterm or SGA birth alone. Conversely, LGA birth lowered the risk for SDD and other emotional and behavioural disorders among individuals born very preterm. In conclusion, PTB along with SGA is associated with higher risks for SDD than one exposure alone, whereas LGA lowers the risks for SDD and other emotional and behavioural disorders in individuals born spontaneously.

Bacterial gut microbiome differences in adults with ADHD and in children with ADHD on psychostimulant medication.

Recent evidence suggests that there is a link between neurodevelopmental disorders, such as attention-deficit hyperactivity disorder (ADHD), and the gut microbiome. However, most studies to date have had low sample sizes, have not investigated the impact of psychostimulant medication, and have not adjusted for potential confounders, including body mass index, stool consistency and diet. To this end, we conducted the largest, to our knowledge, fecal shotgun metagenomic sequencing study in ADHD, with 147 well-characterized adult and child patients. For a subset of individuals, plasma levels of inflammatory markers and short-chain fatty acids were also measured. In adult ADHD patients (n = 84), compared to controls (n = 52), we found a significant difference in beta diversity both regarding bacterial strains (taxonomic) and bacterial genes (functional). In children with ADHD (n = 63), we found that those on psychostimulant medication (n = 33 on medication vs. n = 30 not on medication) had (i) significantly different taxonomic beta diversity, (ii) lower functional and taxonomic evenness, (iii) lower abundance of the strain Bacteroides stercoris CL09T03C01 and bacterial genes encoding an enzyme in vitamin B12 synthesis, and (iv) higher plasma levels of vascular inflammatory markers sICAM-1 and sVCAM-1. Our study continues to support a role for the gut microbiome in neurodevelopmental disorders and provides additional insights into the effects of psychostimulant medication. However, additional studies are needed to replicate these findings and examine causal relationships with the disorder.

Lithium and risk of cardiovascular disease, dementia and venous thromboembolism.

OBJECTIVE: To determine if long-term lithium treatment is associated with protective effects or increased risk of vascular, neurological, and renal disorders. METHODS: Using nationwide registers, we included all citizens of Finland with dispensations of lithium for three or more consecutive years between 1995 and 2016. We identified 9698 cases and matched 96,507 controls without lithium treatment. Studied outcomes were vascular, neurological, renal disorders, and suicide. Analyses were performed applying Cox proportional hazards modeling in full cohort and in further subcohort analysis of individuals with a comparable diagnosis of mood or psychotic disorder. RESULTS: Lithium users had a significantly higher overall disease burden compared to matched population controls, including a higher risk of cardiovascular and cerebrovascular disorders and dementia. However, compared to individuals with a diagnosis of mood or psychotic disorders without lithium treatment, we observed a lower risk of cardiovascular and cerebrovascular disorders (HR = 0.80, 99% CI = 0.73-0.89), and no significant difference for dementia (HR = 1.15, 99% CI = 0.99-1.33), in lithium users. Pulmonary embolism was more common in the lithium-treated cases both in comparison to the general population (HR = 2.86, 99% CI = 2.42-3.37) and in comparison to the psychiatric subcohort (HR = 1.68, 99% CI = 1.31-2.17). Similarly, the risks of Parkinson's disease and kidney disease were higher in both comparisons. CONCLUSIONS: We conclude that individuals prescribed lithium have a lower risk of cardiovascular and cerebrovascular disease, but no marked effect on dementia, compared to individuals with a mood or psychotic disorder not prescribed lithium. Venous thromboembolism, Parkinson's disease, and kidney disease were significantly more prevalent in individuals prescribed lithium.

Exposures during pregnancy and at birth are associated with the risk of offspring eating disorders.

BACKGROUND: Eating disorders (ED) are severe psychiatric disorders, commonly debuting early. Aberrances in the intrauterine environment and at birth have been associated with risk of ED. Here, we explore if, and at what effect size, a variety of such exposures associate with offspring ED, that is, anorexia nervosa (AN), bulimia nervosa (BN), and eating disorder not otherwise specified (EDNOS). METHODS: This population-based cohort study, conducted from September 2021 to August 2023, used Finnish national registries of all live births in 1996-2014 (N = 1,097,753). Cox proportional hazards modeling was used to compare ED risk in exposed versus unexposed offspring, adjusting for potential confounders and performing sex-stratified analyses. RESULTS: A total of 6614 offspring were diagnosed with an ED; 3668 AN, 666 BN, and 4248 EDNOS. Lower risk of offspring AN was seen with young mothers, continued smoking, and instrumental delivery, while higher risk was seen with older mothers, inflammatory disorders, prematurity, small for gestational age, and low Apgar. Offspring risk of BN was higher with continued smoking and prematurity, while lower with postmature birth. Offspring risk of EDNOS was lower with instrumental delivery, higher for older mothers, polycystic ovary syndrome, insulin-treated pregestational diabetes, antibacterial treatment, prematurity, and small for gestational age. Sex-specific associations were found. CONCLUSIONS: Several prenatal and at birth exposures are associated with offspring ED; however, we cannot exclude confounding by maternal BMI. Nevertheless, several exposures selectively associate with risk of either AN, BN, or EDNOS, and some are sex-specific, emphasizing the importance of subtype- and sex-stratified analyses of ED. PUBLIC SIGNIFICANCE: We define environmental factors involved in the development of different ED, of importance as preventive measure, but also in order to aid in defining the molecular pathways involved and thus in the longer perspective contribute to the development of pharmacological treatment of ED.

Association of maternal polycystic ovary syndrome and diabetes with preterm birth and offspring birth size: a population-based cohort study.

STUDY QUESTION: Is the presence of polycystic ovary syndrome (PCOS) associated with more adverse infant outcomes in mothers with different types of diabetes? SUMMARY ANSWER: The presence of PCOS implies higher risks of total (medically indicated and spontaneously combined) and spontaneous preterm birth in mothers with non-insulin-treated type 2 diabetes and gestational diabetes mellitus (GDM), and lower risk of offspring being large for gestational age (LGA) in mothers with insulin-treated diabetes. WHAT IS KNOWN ALREADY: PCOS is suggested to be an independent risk factor for adverse infant outcomes, and it is highly prevalent in mothers with diabetes. However, the impact of PCOS on the associations of different types of maternal diabetes with preterm birth and offspring birth sizes has not been reported. STUDY DESIGN, SIZE, DURATION: This is a population-based cohort study including all live births between 1996 and 2014 in Finland. Children with concurrent maternal diagnoses that could cause signs and symptoms similar to PCOS were excluded. A total of 1 097 753 children were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: National registries were linked to identify births with maternal PCOS (n = 24 682), stratified by diabetes types. Logistic regression was used to examine the association of maternal PCOS and comorbid insulin-treated diabetes, non-insulin-treated type 2 diabetes or GDM with offspring LGA and small for gestational age (SGA). Generalized estimating equation was used to assess the risk of preterm birth in relation to maternal PCOS and diabetes. Potential interaction between PCOS and diabetes was evaluated on both additive and multiplicative scales. MAIN RESULTS AND THE ROLE OF CHANCE: Using mothers with no PCOS and no diabetes as the reference and adjusting for maternal and birth factors, there were higher risks of total (odds ratio (OR) 2.84, 95% CI 2.21 - 3.66 vs. OR 1.91, 95% CI 1.77 - 2.07, P = 0.01) and spontaneous (OR 4.02, 95% CI 2.94 - 5.50 vs. OR 2.35, 95% CI 2.13 - 2.59, P = 0.001) preterm birth for those with PCOS in mothers with non-insulin-treated type 2 diabetes and higher risks of total (OR 1.42, 95% CI 1.27-1.58 vs. OR 0.89, 95% CI 0.86-0.91, P = 0.0001) and spontaneous (OR 1.80, 95% CI 1.59-2.05 vs. OR 1.01, 95% CI 0.98-1.05, P = 0.0001) preterm birth for those with PCOS in mothers with GDM. Among mothers with type 2 diabetes, further adjusting for maternal BMI eliminated the difference in preterm birth risks between those with and those without PCOS, and adjustment for infertility treatment and pre-eclampsia also reduced the preterm risks associated with PCOS significantly. For mothers with GDM, however, the risks of total and spontaneous preterm birth remained higher for those with PCOS following these aforementioned adjustments or stratified analysis. The risk of offspring being LGA was lower for those with PCOS than those without PCOS among mothers with insulin-treated diabetes (OR 18.90, 95% CI 14.21-25.14 vs. OR 32.04, 95% CI 29.79-34.46, P = 0.0001), showing departure from additivity (relative excess risk due to interaction -11.74, 95% CI -16.17 to -7.31, P < 0.001) and multiplicativity (P < 0.001). PCOS did not alter the risk estimate of preterm birth in mothers with insulin-treated diabetes or offspring LGA and SGA in mothers with type 2 diabetes or GDM. LIMITATIONS, REASONS FOR CAUTION: The register-based diagnoses used in this study captured only women with PCOS seeking medical care and having live births. Including female infertility associated with anovulation as PCOS exposure was a risk for misclassification. Sample sizes for pregestational diabetes were small. Insulin purchase during pregnancy in those without a diabetes diagnosis was not accounted for in the analysis. For patients treated with insulin or other medications, we were unable to assess how they complied with such prescriptions. Also, maternal BMI was recorded only once in early pregnancy, thus the potential influence of gestational weight gain on birth outcomes could not be examined. Data on the causes for preterm birth were not available from the registers. WIDER IMPLICATIONS OF THE FINDINGS: The presence of PCOS implied higher risks of total and spontaneous preterm birth in mothers with type 2 diabetes or GDM, and lower risk of offspring being LGA in mothers with insulin-treated diabetes. The higher risks of preterm birth added by PCOS could be explained by prepregnancy BMI or in part by infertility treatment and pre-eclampsia in maternal non-insulin-treated type 2 diabetes, but not in maternal GDM. The differential effects of PCOS on the associations of different types of maternal diabetes with infant outcomes have implications for preventative strategies and clinical counseling for affected pregnancies. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by Shandong Provincial Natural Science Foundation, China (ZR2020MH064 to X.C.), Shandong Province Medical and Health Technology Development Plan (2018WS338 to X.C.), the joint research funding of Shandong University and Karolinska Institute (SDU-KI-2019-08 to X.C. and C.L.), the Finnish National Institute for Health and Welfare: Drug and pregnancy project (M.G.), the Swedish Research Council (2014-10171 to C.L.), the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institute Stockholm County Council (SLL20170292 and SLL20190589 to C.L.), the Swedish Brain Foundation (FO2019-0201 and FO2020-0305 to C.L.). X.C. received grants from the China Scholarship Council at the beginning of the study. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression.

Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10-4 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 × 10-7). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.

Sirtuins and neuropeptide y downregulation in Flinders Sensitive Line rat model of depression.

Since the NAD+-dependent histone deacetylases sirtuin-1 (SIRT1) and sirtuin-2 (SIRT2) are critically involved in epigenetics, endocrinology and immunology and affect the longevity in model organisms, we investigated their expression in brains of 3-month-old and 14-15 months old rat model of depression Flinders Sensitive Line (FSL) and control Flinders Resistant Line (FRL) rats. In view of the dysregulated NPY system in depression, we also studied NPY in young and old FSL to explore the temporal trajectory of depressive-like-ageing interaction. Sirt1, Sirt2 and Npy mRNA were determined using qRT-PCR in prefrontal cortex (PFC) from young and old FSL and FRL, and in hippocampi from young FSL and FRL. PFC: Sirt1 expression was decreased in FSL (p = 0.001). An interaction between age and genotype was found (p = 0.032); young FSL had lower Sirt1 with respect to both age (p = 0.026) and genotype (p = 0.001). Sirt2 was lower in FSL (p = 0.003). Npy mRNA was downregulated in FSL (p = 0.001) but did not differ between the young and old rat groups. Hippocampus: Sirt1 was reduced in young FSL compared to young FRL (p = 0.005). There was no difference in Sirt2 between FSL and FRL. Npy levels were decreased in hippocampus of young FSL compared to young FRL (p = 0.003). Effects of ageing could not be investigated due to loss of samples. To conclude, i this is the first demonstration that SIRT1 and SIRT2 are changed in brain of FSL, a rat model of depression; ii the changes are age-dependent; iii sirtuins are potential targets for treatment of age-related neurodegenerative diseases.

Association of maternal polycystic ovary syndrome or anovulatory infertility with obesity and diabetes in offspring: a population-based cohort study.

STUDY QUESTION: Are children of mothers with polycystic ovary syndrome (PCOS) or anovulatory infertility at increased risks of obesity or diabetes? SUMMARY ANSWER: Maternal PCOS/anovulatory infertility is associated with an increased risk of offspring obesity from early age and diabetes in female offspring from late adolescence. WHAT IS KNOWN ALREADY: Women with PCOS often have comorbid metabolic disorders such as obesity and diabetes, and children of mothers with PCOS have an increased risk of subtle signs of cardiometabolic alterations. STUDY DESIGN, SIZE, DURATION: This was a nationwide cohort study of all live births (n = 1 105 997) during 1996-2014 in Finland, excluding those with maternal diagnoses sharing signs and symptoms with PCOS (n = 8244). A total of 1 097 753 births were included and followed up until 31 December 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: National registries were linked to identify births with maternal PCOS or anovulatory infertility (n = 24 682). The primary outcomes were diagnoses of obesity (ICD-10: E65, E66) and diabetes (ICD-10: E10-E14) in offspring recorded in the Finnish Care Register for Health Care. Cox proportional hazards regression was modeled to analyze the risk of offspring obesity and diabetes in relation to prenatal exposure to maternal PCOS/anovulatory infertility. Differently adjusted models and stratified analyses were used to assess whether the risk was modified by maternal obesity or diabetes diagnoses, pre-pregnancy BMI, fertility treatment or perinatal problems. MAIN RESULTS AND THE ROLE OF CHANCE: Exposure to maternal PCOS/anovulatory infertility was associated with a higher cumulative incidence of obesity in the children (exposed: 1.83%; 95% CI 1.66-2.00% vs unexposed: 1.24%; 95% CI 1.22-1.26%). Accounting for birth factors and maternal characteristics such as obesity and diabetes diagnoses, the hazard ratio (HR) for obesity was increased in offspring below 9 years of age (HR 1.58; 95% CI 1.30-1.81), and in those 10-16 years of age (HR 1.37; 95% CI 1.19-1.57), but not in those aged 17-22 years (HR 1.24; 95% CI 0.73-2.11). Sex-stratified analyses revealed similar risk estimates for boys (HR 1.48; 95% CI 1.31-1.68) and girls (HR 1.45; 95% CI 1.26-1.68). Notably, the joint effect of PCOS/anovulatory infertility and BMI-based pre-pregnancy obesity on offspring obesity (HR 8.89; 95% CI 7.06-11.20) was larger than that of either PCOS/anovulatory infertility or obesity alone. Furthermore, PCOS/anovulatory infertility was associated with offspring obesity in children without perinatal problems (HR 1.27; 95% CI 1.17-1.39), with larger effect size for maternal PCOS/anovulatory infertility and joint perinatal problems (HR 1.61; 95% CI 1.35-1.91). However, the risk estimates were comparable between maternal PCOS/anovulatory infertility with (HR 1.54; 95% CI 1.17-2.03) and without fertility treatment (HR 1.46; 95% CI 1.32-1.61). For offspring diabetes, the HR was increased only between 17 and 22 years of age (HR 2.06; 95% CI 1.23-3.46), and specifically for Type 1 diabetes in females (HR 3.23; 95% CI 1.41-7.40). LIMITATIONS, REASONS FOR CAUTION: The prevalence of PCOS/anovulatory infertility in this study was 2.2%, lower than that reported in previous studies. In addition, the incidence of obesity in offspring was lower than that reported in studies based on measured or self-reported weight and height and may include mainly moderate and severe obesity cases who needed and/or actively sought medical care. Moreover, mothers with PCOS/anovulatory infertility were identified based on ICD codes, with no information on PCOS phenotypes. Furthermore, maternal pre-pregnancy BMI was available only from 2004. The PCOS/anovulatory infertility association with female offspring diabetes was based on only a few cases. Mothers' weight gain during pregnancy, use of fertility treatment other than fresh or frozen IVF/ICSI, offspring lifestyle, as well as fathers' age, medical disorders or medication prescriptions were not available for this study. WIDER IMPLICATIONS OF THE FINDINGS: These findings support that prenatal PCOS/anovulatory infertility exposure influences metabolic health in the offspring from early age. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by Shandong Provincial Natural Science Foundation, China [ZR2020MH064 to X.C.], Shandong Province Medical and Health Technology Development Plan [2018WS338 to X.C.], the joint research funding of Shandong University and Karolinska Institute [SDU-KI-2019-08 to X.C. and C.L.], the Finnish Institute for Health and Welfare: Drug and Pregnancy Project [M.G.], the Swedish Research Council [2014-10171 to C.L.], the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institute Stockholm County Council [SLL20170292 and SLL20190589 to C.L.], the Swedish Brain Foundation [FO2018-0141 and FO2019-0201 to C.L.]. X.C. received grants from the China Scholarship Council at the beginning of the study. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Enteric short-chain fatty acids promote proliferation of human neural progenitor cells.

Short-chain fatty acids (SCFAs) are a group of fatty acids predominantly produced during the fermentation of dietary fibers by the gut anaerobic microbiota. SCFAs affect many host processes in health and disease. SCFAs play an important role in the 'gut-brain axis', regulating central nervous system processes, for example, cell-cell interaction, neurotransmitter synthesis and release, microglia activation, mitochondrial function, and gene expression. SCFAs also promote the growth of neurospheres from human neural stem cells and the differentiation of embryonic stem cells into neural cells. It is plausible that maternally derived SCFAs may pass the placenta and expose the fetus at key developmental periods. However, it is unclear how SCFA exposure at physiological levels influence the early-stage neural cells. In this study, we explored the effect of SCFAs on the growth rate of human neural progenitor cells (hNPCs), generated from human embryonic stem cell line (HS980), with IncuCyte live-cell analysis system and immunofluorescence. We found that physiologically relevant levels (µM) of SCFAs (acetate, propionate, butyrate) increased the growth rate of hNPCs significantly and induced more cells to undergo mitosis, while high levels (mM) of SCFAs had toxic effects on hNPCs. Moreover, no effect on apoptosis was observed in physiological-dose SCFA treatments. In support, data from q-RT PCR showed that SCFA treatments influenced the expression of the neurogenesis, proliferation, and apoptosis-related genes ATR, BCL2, BID, CASP8, CDK2, E2F1, FAS, NDN, and VEGFA. To conclude, our results propose that SCFAs regulates early neural system development. This might be relevant for a putative 'maternal gut-fetal brain-axis'. Cover Image for this issue: doi: 10.1111/jnc.14761.

Relationship of prenatal maternal obesity and diabetes to offspring neurodevelopmental and psychiatric disorders: a narrative review.

Obesity and diabetes is a worldwide public health problem among women of reproductive age. This narrative review highlights recent epidemiological studies regarding associations of maternal obesity and diabetes with neurodevelopmental and psychiatric disorders in offspring, and provides an overview of plausible underlying mechanisms and challenges for future human studies. A comprehensive search strategy selected terms that corresponded to the domains of interest (maternal obesity, different types of diabetes, offspring cognitive functions and neuropsychiatric disorders). The databases searched for articles published between January 2010 and April 2019 were PubMed, Web of Science and CINAHL. Evidence from epidemiological studies strongly suggests that maternal pre-pregnancy obesity is associated with increased risks for autism spectrum disorder, attention-deficit hyperactivity disorder and cognitive dysfunction with modest effect sizes, and that maternal diabetes is associated with the risk of the former two disorders. The influence of maternal obesity on other psychiatric disorders is less well studied, but there are reports of associations with increased risks for offspring depression, anxiety, schizophrenia and eating disorders, at modest effect sizes. It remains unclear whether these associations are due to intrauterine mechanisms or explained by confounding family-based sociodemographic, lifestyle and genetic factors. The plausible underlying mechanisms have been explored primarily in animal models, and are yet to be further investigated in human studies.

Association of polycystic ovary syndrome or anovulatory infertility with offspring psychiatric and mild neurodevelopmental disorders: a Finnish population-based cohort study.

STUDY QUESTION: Is maternal polycystic ovary syndrome (PCOS) associated with increased risks for a broad spectrum of psychiatric and mild neurodevelopmental disorders in offspring? SUMMARY ANSWER: Maternal PCOS and/or anovulatory infertility is independently, and jointly with maternal obesity, perinatal problems, cesarean delivery and gestational diabetes, associated with increased risks in offspring for almost all groups of psychiatric and mild neurodevelopmental disorders with onset in childhood or adolescence. WHAT IS KNOWN ALREADY: Maternal PCOS was previously associated with autism spectrum disorder, attention-deficit/hyperactivity disorders and possibly developmental delay in offspring. Few studies have investigated the association between maternal PCOS and other psychiatric and neurodevelopmental disorders in offspring. STUDY DESIGN, SIZE, DURATION: This was a population-based cohort study in Finland including all live births between 1996 and 2014 (n = 1 105 997). After excluding births to mothers with symptoms similar to PCOS, a total of 1 097 753 births by 590 939 mothers remained. Children were followed up until 31 December 2018, i.e. up to the age of 22 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: National registries were used to link data of the included births and their mothers. Data from 24 682 (2.2%) children born to mothers with PCOS were compared with 1 073 071 (97.8%) children born to mothers without PCOS. Cox proportional hazards modeling was used to evaluate the hazard ratio (HR) and 95% CI for the risk of neuropsychiatric disorders in relation to maternal PCOS. Stratified analyses were performed to test the independent role of PCOS and the joint effects of PCOS with maternal obesity, perinatal problems, cesarean delivery, gestational diabetes and use of fertility treatment. The analysis was adjusted for maternal age, country of birth, marriage status at birth, smoking, parity, psychiatric disorders, prescription of psychotropic N05/N06 during pregnancy and systemic inflammatory diseases when applicable. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 105 409 (9.8%) children were diagnosed with a neurodevelopmental or psychiatric disorder. Firstly, maternal PCOS was associated with any psychiatric diagnosis (HR 1.32; 95% CI 1.27-1.38) in offspring. Particularly, the risk was increased for sleeping disorders (HR 1.46; 95% CI 1.27-1.67), attention-deficit/hyperactivity disorders and conduct disorders (HR 1.42; 95% CI 1.33-1.52), tic disorders (HR 1.42; 95% CI 1.21-1.68), intellectual disabilities (HR 1.41; 95% CI 1.24-1.60), autism spectrum disorder (HR 1.40; 95% CI 1.26-1.57), specific developmental disorders (HR 1.37; 95% CI 1.30-1.43), eating disorders (HR 1.36; 95% CI 1.15-1.61), anxiety disorders (HR 1.33; 95% CI 1.26-1.41), mood disorders (HR 1.27; 95% CI 1.18-1.35) and other behavioral and emotional disorders (ICD-10 F98, HR 1.49; 95% CI 1.39-1.59). In short, there was no significant difference between sexes. The results were robust when restricting the analyses to the first-born children or births to mothers without psychiatric diagnosis or purchase of psychotropic medication. Secondly, stratified analysis according to maternal BMI showed that the risk of any neuropsychiatric disorder was increased in offspring to normal-weight mothers with PCOS (HR 1.20; 95% CI 1.09-1.32), and markedly higher in those to severely obese mothers with PCOS (HR 2.11; 95% CI 1.76-2.53) compared to offspring to normal-weight mothers without PCOS. When excluding perinatal problems, mothers with PCOS were still associated with increased risks of any neuropsychiatric disorders in offspring (HR 1.28; 95% CI 1.22-1.34) compared to mothers without PCOS. However, an additional increase was observed for PCOS in combination with perinatal problems (HR 1.99; 95% CI 1.84-2.16). Likewise, excluding cases with maternal gestational diabetes (HR 1.30; 95% CI 1.25-1.36), cesarean delivery (HR 1.29; 95% CI 1.23-1.35) or fertility treatment (HR 1.31; 95% CI 1.25-1.36) did not eliminate the associations. LIMITATIONS, REASONS FOR CAUTION: The register-based prevalence of PCOS was lower than previously reported, suggesting that this study may capture the most severe cases. To combine anovulatory infertility with PCOS diagnosis as PCOS exposure might introduce diagnostic bias. It was not feasible to distinguish between subtypes of PCOS. Furthermore, familial factors might confound the association between maternal PCOS and neuropsychiatric disorders in offspring. Maternal BMI was available for birth cohort 2004-2014 only and there was no information on gestational weight gain. WIDER IMPLICATIONS OF THE FINDINGS: This study provides further evidence that maternal PCOS and/or anovulatory infertility, independently and jointly with maternal obesity, perinatal problems, gestational diabetes and cesarean delivery, implies a broad range of adverse effects on offspring neurodevelopment. These findings may potentially help in counseling and managing pregnancies. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the joint research funding of Shandong University and Karolinska Institute (SDU-KI-2019-08 to X.C and C.L.), THL Finnish Institute for Health and Welfare: Drug and pregnancy project [M.G.], the Swedish Research Council [2014-10171 to C.L.], the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institute Stockholm County Council [SLL20170292 to C.L.], the Swedish Brain Foundation [FO2018-0141 and FO2019-0201 to C.L.]. X.C. was supported by the China Scholarship Council during her training in Karolinska Institute. L.K. was supported by the China Scholarship Council for his PhD study in Karolinska Institute. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Effects of a synbiotic on symptoms, and daily functioning in attention deficit hyperactivity disorder - A double-blind randomized controlled trial.

Some prebiotics and probiotics have been proposed to improve psychiatric symptoms in children with autism. However, few studies were placebo-controlled, and there is no study on persons with an attention deficit hyperactivity disorder (ADHD) diagnosis. Our aim was to study effects of Synbiotic 2000 on psychiatric symptoms and functioning in children and adults with ADHD without an autism diagnosis. Children and adults (n = 182) with an ADHD diagnosis completed the nine weeks randomized double-blind parallel placebo-controlled trial examining effects of Synbiotic 2000 on the primary endpoints ADHD symptoms, autism symptoms and daily functioning, and the secondary endpoint emotion regulation, measured using the questionnaires SNAP-IV, ASRS, WFIRS, SCQ, AQ and DERS-16. Levels at baseline of plasma C-reactive protein and soluble vascular cell adhesion molecule-1 (sVCAM-1), central to leukocyte-endothelial cell adhesion facilitating inflammatory responses in tissues, were measured using Meso Scale Discovery. Synbiotic 2000 and placebo improved ADHD symptoms equally well, and neither active treatment nor placebo had any statistically significant effect on functioning or sub-diagnostic autism symptoms. However, Synbiotic 2000, specifically, reduced sub-diagnostic autism symptoms in the domain restricted, repetitive and stereotyped behaviors in children, and improved emotion regulation in the domain of goal-directed behavior in adults. In children with elevated sVCAM-1 levels at baseline as well as in children without ADHD medication, Synbiotic 2000 reduced both the total score of autism symptoms, and the restricted, repetitive and stereotyped behaviors. In adults with elevated sVCAM-1 at baseline, Synbiotic 2000 significantly improved emotion regulation, both the total score and four of the five subdomains. To conclude, while no definite Synbiotic 2000-specific effect was detected, the analysis of those with elevated plasma sVCAM-1 levels proposed a reduction of autism symptoms in children and an improvement of emotion regulation in adults with ADHD. Trial registration number: ISRCTN57795429.

Genetics of response to cognitive behavior therapy in adults with major depression: a preliminary report.

Major depressive disorder is heritable and a leading cause of disability. Cognitive behavior therapy is an effective treatment for major depression. By quantifying genetic risk scores based on common genetic variants, the aim of this report was to explore the utility of psychiatric and cognitive trait genetic risk scores, for predicting the response of 894 adults with major depressive disorder to cognitive behavior therapy. The participants were recruited in a psychiatric setting, and the primary outcome score was measured using the Montgomery Åsberg Depression Rating Scale-Self Rated. Single-nucleotide polymorphism genotyping arrays were used to calculate the genomic risk scores based on large genetic studies of six phenotypes: major depressive disorder, bipolar disorder, attention-deficit/hyperactivity disorder, autism spectrum disorder, intelligence, and educational attainment. Linear mixed-effect models were used to test the relationships between the six genetic risk scores and cognitive behavior therapy outcome. Our analyses yielded one significant interaction effect (B = 0.09, p < 0.001): the autism spectrum disorder genetic risk score correlated with Montgomery Åsberg Depression Rating Scale-Self Rated changes during treatment, and the higher the autism spectrum disorder genetic load, the less the depressive symptoms decreased over time. The genetic risk scores for the other psychiatric and cognitive traits were not related to depressive symptom severity or change over time. Our preliminary results indicated, as expected, that the genomics of the response of patients with major depression to cognitive behavior therapy were complex and that future efforts should aim to maximize sample size and limit subject heterogeneity in order to gain a better understanding of the use of genetic risk factors to predict treatment outcome.

Association of Catechol-O-methyltransferase (COMT Val158Met) with future risk of cardiovascular disease in depressed individuals - a Swedish population-based cohort study.

BACKGROUND: Catechol-O-methyltransferase (COMT Val158Met) has been implicated in both depression and cardiovascular disease. The purpose of this study was to assess if COMT Val158Met, which influences the COMT enzyme activity, has an effect on the risk of cardiovascular disease (CVD) in individuals with a history of depression and also to determine if the risk differs depending on gender. METHODS: Data from a longitudinal cohort study of mental health among Swedish adults was used. Depression was assessed twice 3 years apart for each participant, in 1998-2001 and 2001-2003. Saliva DNA was contributed by 4349 (41.7%) of the participants and 3525 was successfully genotyped for COMT Val158Met. Participants were followed up until December 2014 from the National Patient register with regard to cardiovascular outcomes (hypertensive or ischemic heart disease, and stroke). RESULTS: Those with depression and the high COMT enzyme activity genotype (Val/Val) had almost a three-fold increased risk of later CVD (OR 3.6; 95% CI: 2.0-6.6) compared to those non-depressed carrying the Val/Val allele. This effect on risk for CVD was higher in women compared to men (OR 7.0; 95% CI: 3.0-14.0 versus OR 2.1; 95% CI: 1.0-6.8). Both additive interaction (attributable proportion (AP) = 0.56; 95% CI: 0.24-0.90 and synergy index (SI) = 4.39; 1.0-18.7) and multiplicative interaction (log likelihood test p = 0.1) was present between depression and COMT Val158Met in predicting risk of later CVD. CONCLUSION: High COMT activity genotype Val158Met increased the risk of CVD in depressed persons. The risk was higher in women compared to men.

Effects of internet-based cognitive behavioural therapy and physical exercise on sick leave and employment in primary care patients with depression: two subgroup analyses.

OBJECTIVES: Depression can negatively impact work capacity, but treatment effects on sick leave and employment are unclear. This study evaluates if internet-based cognitive behavioural therapy (ICBT) or physical exercise (PE), with already reported positive effects on clinical outcome and short-term work ability, has better effects on employment, sick leave and long-term work ability compared with treatment as usual (TAU) for depressed primary care patients (German clinical trials: DRKS00008745). METHODS: After randomisation and exclusion of patients not relevant for work-related analysis, patients were divided into two subgroups: initially unemployed (total n=118) evaluated on employment, and employed (total n=703) evaluated on long-term sick leave. Secondary outcomes were self-rated work ability and average number of sick days per month evaluated for both subgroups. Assessments (self-reports) were made at baseline and follow-up at 3 and 12 months. RESULTS: For the initially unemployed subgroup, 52.6% were employed after 1 year (response rate 82%). Both PE (risk ratio (RR)=0.44; 95% CI 0.23 to 0.87) and ICBT (RR=0.37; 95% CI 0.16 to 0.84) showed lower rates compared with TAU after 3 months, but no difference was found after 1 year (PE: RR=0.97; 95% CI 0.69 to 1.57; ICBT: RR=1.23; 95% CI 0.72 to 2.13). For those with initial employment, long-term sick leave (response rate 75%) decreased from 7.8% to 6.5%, but neither PE (RR=1.4; 95% CI 0.52 to 3.74) nor ICBT (RR=0.99; 95% CI 0.39 to 2.46) decreased more than TAU, although a temporary positive effect for PE was found. All groups increased self-rated work ability with no differences found. CONCLUSIONS: No long-term effects were found for the initially unemployed on employment status or for the initially employed on sick leave. New types of interventions need to be explored.

MicroRNA 101b Is Downregulated in the Prefrontal Cortex of a Genetic Model of Depression and Targets the Glutamate Transporter SLC1A1 (EAAT3) in Vitro.

BACKGROUND: MicroRNAs (miRNAs) are small regulatory molecules that cause translational repression by base pairing with target mRNAs. Cumulative evidence suggests that changes in miRNA expression may in part underlie the pathophysiology and treatment of neuropsychiatric disorders, including major depressive disorder (MDD). METHODS: A miRNA expression assay that can simultaneously detect 423 rat miRNAs (miRBase v.17) was used to profile the prefrontal cortex (PFC) of a genetic rat model of MDD (the Flinders Sensitive Line [FSL]) and the controls, the Flinders Resistant Line (FRL). Gene expression data from the PFC of FSL/FRL animals (GEO accession no. GSE20388) were used to guide mRNA target selection. Luciferase reporter assays were used to verify miRNA targets in vitro. RESULTS: We identified 23 miRNAs that were downregulated in the PFC of the FSL model compared with controls. Interestingly, one of the identified miRNAs (miR-101b) is highly conserved between rat and human and was recently found to be downregulated in the PFC of depressed suicide subjects. Using a combination of in silico and in vitro analyses, we found that miR-101b targets the neuronal glutamate transporter SLC1A1 (also known as EAAC1 or EAAT3). Accordingly, both mRNA and protein levels of SLC1A1 were found to be upregulated in the PFC of the FSL model. CONCLUSIONS: Besides providing a list of novel miRNAs associated with depression-like states, this preclinical study replicated the human association of miR-101 with depression. In addition, since one of the targets of miR-101b appears to be a glutamate transporter, our preclinical data support the hypothesis of a glutamatergic dysregulation being implicated in the etiology of depression.

TERT rs2736100 genotypes are associated with differential risk of myeloproliferative neoplasms in Swedish and Chinese male patient populations.

The telomerase reverse transcriptase (TERT) gene rs2736100_C allele has recently been shown to be associated with an increased risk for myeloproliferative neoplasms (MPNs) among Caucasians. However, it is unknown if this association is present in other ethnical populations and whether rs2736100 allele frequencies mirror the incidence of MPNs in a population. Here we genotyped TERT rs2736100 variants in 126 Swedish and 101 Chinese MPN patients and their age-, sex-, and ethnically-matched healthy controls. Healthy Chinese adults had a higher frequency of the A allele and lower frequencies of the C allele compared to Swedish counterparts (57.4 vs 47.0 % for A, 42.6 vs 53.0 % for C, P = 0.006). Both Swedish and Chinese patients harbored significantly higher C allele frequency than their controls (62.7 vs 53.0 % and 57.4 vs 42.6 % for Swedish and Chinese, respectively, P = 0.004). Swedes and Chinese bearing the CC genotype had a significantly increased risk of MPN compared to AA carriers (OR = 2.47; 95 % CI: 1.33-4.57, P = 0.003, for Swedes, and OR = 3.45; 95 % CI: 1.52-7.85, P = 0.005, for Chinese). Further analyses showed that rs2736100_CC was associated with robustly enhanced risk in males only (CC vs AA, OR = 5.11; 95 % CI: 2.19-11.92, P < 0.0001). The CC-carrying MPN patients exhibited significantly higher TERT expression than patients with the AC genotype. Collectively, the rs2736100_C is a risk allele for MPNs in Swedish and Chinese males, and the lower incidence of MPNs in the Chinese population is correlated with a lower rs2736100_C risk allele frequency.