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Abstract Background Many bipolar patients (BP) are affected by cognitive impairments and reduced psychosocial function even after complete remission. In the present naturalistic study, we developed a tailored cognitive remediation program (CR) to evaluate the effect on objective and subjective neuropsychological performance, psychosocial functioning and quality of life. Methods The CR program used a cognitive training software combined with group sessions to educate cognitive skills. 102 BP were screened by a neuropsychological test battery. Of those, 39 BP showed distinct cognitive impairments and 26 patients of them participated in the CR program for 12 weeks and then were retested. A matched control group consisting of 10 BP was measured at baseline and follow-up after three months (treatment as usual). Results Within the training group, a significant improvement of cognitive performance after CR was observed in working memory (p = .043), problem solving (p = .031) and divided attention (trend, p = .065). The control group did not improve in any test measure. In addition, we detected a significant reduction of sub-depressive symptoms (p = .011) after the CR program. However, there was no change in psychosocial functioning and quality of life. Subjective cognitive complaints were not associated with objective test performance. Limitations As we included exclusively BP with objectively assessed neurocognitive deficits, recruitment was difficult and subsequently we had a small sample size and were not able to implement a randomized group design. Conclusions Our results suggest that BP with objective cognitive impairments could benefit from CR potentially with regard to executive functioning. Furthermore, there is preliminary evidence that CR could have a positive effect on subthreshold residual symptoms. However, to fully identify the possible implications of CR in bipolar disorder, larger randomized-controlled trials are needed in this new field of research.

Aerosol heating due to shortwave absorption has implications for local atmospheric stability and regional dynamics. The derivation of heating rate profiles from space-based observations is challenging because it requires the vertical profile of relevant properties such as the aerosol extinction coefficient and single-scattering albedo (SSA). In the southeastern Atlantic, this challenge is amplified by the presence of stratocumulus clouds below the biomass burning plume advected from Africa, since the cloud properties affect the magnitude of the aerosol heating aloft, which may in turn lead to changes in the cloud properties and life cycle. The combination of spaceborne lidar data with passive imagers shows promise for future derivations of heating rate profiles and curtains, but new algorithms require careful testing with data from aircraft experiments where measurements of radiation, aerosol, and cloud parameters are better colocated and readily available. In this study, we derive heating rate profiles and vertical cross sections (curtains) from aircraft measurements during the NASA ObseRvations of Aerosols above CLouds and their intEractionS (ORACLES) project in the southeastern Atlantic. Spectrally resolved irradiance measurements and the derived column absorption allow for the separation of total heating rates into aerosol and gas (primarily water vapor) absorption. The nine cases we analyzed capture some of the co-variability of heating rate profiles and their primary drivers, leading to the development of a new concept: the heating rate efficiency (HRE; the heating rate per unit aerosol extinction). HRE, which accounts for the overall aerosol loading as well as vertical distribution of the aerosol layer, varies little with altitude as opposed to the standard heating rate. The large case-to-case variability for ORACLES is significantly reduced after converting from heating rate to HRE, allowing us to quantify its dependence on SSA, cloud albedo, and solar zenith angle.

In this paper, we use observations from the NASA ORACLES (ObseRvations of CLouds above Aerosols and their intEractionS) aircraft campaign to develop a framework by way of two parameterizations that establishes regionally representative relationships between aerosol-cloud properties and their radiative effects. These relationships rely on new spectral aerosol property retrievals of the single scattering albedo (SSA) and asymmetry parameter (ASY). The retrievals capture the natural variability of the study region as sampled, and both were found to be fairly narrowly constrained (SSA: 0.83 ± 0.03 in the mid-visible, 532 nm; ASY: 0.54 ± 0.06 at 532 nm). The spectral retrievals are well suited for calculating the direct aerosol radiative effect (DARE) since SSA and ASY are tied directly to the irradiance measured in the presence of aerosols – one of the inputs to the spectral DARE. The framework allows for entire campaigns to be generalized into a set of parameterizations. For a range of solar zenith angles, it links the broadband DARE to the mid-visible aerosol optical depth (AOD) and the albedo (α) of the underlying scene (either clouds or clear sky) by way of the first parameterization: P(AOD, α). For ORACLES, the majority of the case-to-case variability of the broadband DARE is attributable to the dependence on the two driving parameters of P(AOD, α). A second, extended, parameterization PX(AOD, α, SSA) explains even more of the case-to-case variability by introducing the mid-visible SSA as a third parameter. These parameterizations establish a direct link from two or three mid-visible (narrowband) parameters to the broadband DARE, implicitly accounting for the underlying spectral dependencies of its drivers. They circumvent some of the assumptions when calculating DARE from satellite products or in a modeling context. For example, the DARE dependence on aerosol microphysical properties is not explicit in P or PX because the asymmetry parameter varies too little from case to case to translate into appreciable DARE variability. While these particular DARE parameterizations only represent the ORACLES data, they raise the prospect of generalizing the framework to other regions.

Determining the direct aerosol radiative effect (DARE) of absorbing aerosols above clouds from satellite observations alone is a challenging task, in part because the radiative signal of the aerosol layer is not easily untangled from that of the clouds below. In this study, we use aircraft measurements from the NASA ObseRvations of CLouds above Aerosols and their intEractionS (ORACLES) project in the southeastern Atlantic to derive it with as few assumptions as possible. This is accomplished by using spectral irradiance measurements (Solar Spectral Flux Radiometer, SSFR) and aerosol optical depth (AOD) retrievals (Spectrometer for Sky-Scanning, Sun-Tracking Atmospheric Research, 4STAR) during vertical profiles (spirals) that minimize the albedo variability of the underlying cloud field – thus isolating aerosol radiative effects from those of the cloud field below. For two representative cases, we retrieve spectral aerosol single scattering albedo (SSA) and the asymmetry parameter (g) from these profile measurements and calculate DARE given the albedo range measured by SSFR on horizontal legs above clouds. For mid-visible wavelengths, we find SSA values from 0.80 to 0.85 and a significant spectral dependence of g. As the cloud albedo increases, the aerosol increasingly warms the column. The transition from a cooling to a warming top-of-aerosol radiative effect occurs at an albedo value (critical albedo) just above 0.2 in the mid-visible wavelength range. In a companion paper, we use the techniques introduced here to generalize our findings to all 2016 and 2017 measurements and parameterize aerosol radiative effects.

Eight ruminally-fistulated wethers were used to examine the temporal effects of afternoon (PM; 1600h) v. morning (AM; 0800 h) allocation of fresh spring herbage from a perennial ryegrass (Lolium perenne L.)-based pasture on fermentation and microbial community dynamics. Herbage chemical composition was minimally affected by time of allocation, but daily mean ammonia concentrations were greater for the PM group. The 24-h pattern of ruminal fermentation (i.e. time of sampling relative to time of allocation), however, varied considerably for all fermentation variables (P⩽0.001). Most notably amongst ruminal fermentation characteristics, ammonia concentrations showed a substantial temporal variation; concentrations of ammonia were 1.7-, 2.0- and 2.2-fold greater in rumens of PM wethers at 4, 6 and 8h after allocation, respectively, compared with AM wethers. The relative abundances of archaeal and ciliate protozoal taxa were similar across allocation groups. In contrast, the relative abundances of members of the rumen bacterial community, like Prevotella 1 (P=0.04), Bacteroidales RF16 group (P=0.005) and Fibrobacter spp. (P=0.008) were greater for the AM group, whereas the relative abundance of Kandleria spp. was greater (P=0.04) for the PM group. Of these taxa, only Prevotella 1 (P=0.04) and Kandleria (P

The influence of stationary spatially homogeneous Townsend discharge on the (1 0 0) surface of semi-insulating GaAs samples is studied. Samples exposed to both electrons and ions in a nitrogen discharge at a current density j = 60 uA cm[?]2 are studied by means of x-ray photoelectron spectroscopy, ellipsometry and atomic force microscopy. It is shown that an exposure to low-energy ions (<1 eV) changes the crystal structure of the semiconductor for a depth of up to 10-20 nm, although the stoichiometric composition does not change. The exposure to low-energy electrons (<10 eV) forms an oxide layer, which is 5-10 nm thick. Atomic force microscopy demonstrates that the change in the surface potential of the samples may exceed 100 mV, for both discharge polarities, while the surface roughness does not increase. [ABSTRACT FROM AUTHOR]

Bipolar disorder is a leading contributor to the global burden of disease 1 . Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown 2 . We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings 3 , and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder 4 , highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder., Competing Interests: Competing interests: T.E.T., H. Stefansson and K.S. are employed by deCODE Genetics/Amgen. E.A.S. is an employee of Regeneron Genetics Center and owns stocks of Regeneron Pharmaceutical. K.-H.L. and X.W. are employed by 23andMe. Multiple additional authors work for pharmaceutical or biotechnology companies in a manner directly analogous to academic co-authors and collaborators. A.H.Y. has given paid lectures and served on advisory boards relating to drugs used in affective and related disorders for several companies (AstraZeneca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allergan, Bionomics and Sumitomo Dainippon Pharma), was Lead Investigator for the Embolden study (AstraZeneca), BCI Neuroplasticity study and Aripiprazole Mania study, and is an investigator for Janssen, Lundbeck, Livanova and Compass. J.I.N. is an investigator for Janssen. P.F.S. is on the advisory committee and a shareholder of Neumora Therapeutics. G.B. reports consultancy and speaker fees from Eli Lilly and Illumina, and grant funding from Eli Lilly. M. Landén has received speaker fees from Lundbeck. O.A.A. has served as a speaker for Janssen, Lundbeck and Sunovion, and as a consultant for Cortechs.ai. A.M.D. is a founder of and holds equity interest in CorTechs Labs and serves on its scientific advisory board; is a member of the scientific advisory board of Human Longevity and the Mohn Medical Imaging and Visualization Center; and has received research funding from General Electric Healthcare. E.V. has received grants and served as a consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbott, Allergan, Angelini, AstraZeneca, Bristol Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, GlaxoSmithKline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, SAGE, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Catalan Government (AGAUR and PERIS), the Spanish Ministry of Science, Innovation, and Universities (AES and CIBERSAM), the Seventh European Framework Programme and Horizon 2020 and the Stanley Medical Research Institute. S.K.-S. received author’s, speaker’s and consultant honoraria from Janssen, Medice Arzneimittel Pütter GmbH and Takeda outside of the current work. A. Serretti is or has been a consultant and/or speaker for: Abbott, AbbVie, Angelini, AstraZeneca, Clinical Data, Boheringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi and Servier. J.R.D. has served as an unpaid consultant to Myriad-Neuroscience (formerly Assurex Health) in 2017 and 2019, and owns stock in CVS Health. B.M.N. is a member of the scientific advisory board at Deep Genomics, and consultant for Camp4 Therapeutics, Takeda Pharmaceutical and Biogen. B.-C.L., J.-W.K., Y.K.L., J.H.K., M. J. Cheon and D.J.K. are employed by Genoplan. I.B.H. is the Co-Director of Health and Policy at the Brain and Mind Centre (BMC) University of Sydney. The BMC operates an early-intervention youth services at Camperdown under contract to Headspace. I.B.H. is also the Chief Scientific Advisor to, and a 3.2% equity shareholder in, InnoWell. InnoWell was formed by the University of Sydney (45% equity) and PwC (Australia; 45% equity) to deliver the $30 M (AUD) Australian Government-funded Project Synergy (2017–2020; a 3-year program for the transformation of mental health services) and to lead transformation of mental health services internationally through the use of innovative technologies. M.J.O. and M.C.O. have received funding from Takeda Pharmaceuticals and Akrivia Health outside the scope of the current work. P. B. Mitchell. has received remuneration from Janssen (Australia) and Sanofi (Hangzhou) for lectures or advisory board membership. J.A.R.-Q. was on the speakers’ bureau and/or acted as consultant for Biogen, Idorsia, Casen-Recordati, Janssen-Cilag, Novartis, Takeda, Bial, Sincrolab, Neuraxpharm, Novartis, BMS, Medice, Rubió, Uriach, Technofarma and Raffo in the past 3 years; has also received travel awards (airplane tickets and hotel) for taking part in psychiatric meetings from Idorsia, Janssen-Cilag, Rubió, Takeda, Bial and Medice; and the Department of Psychiatry chaired by J.A.R.-Q. received unrestricted educational and research support from the following companies in the past 3 years: Exeltis, Idorsia, Janssen-Cilag, Neuraxpharm, Oryzon, Roche, Probitas and Rubió. All other authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature Limited.)

Background and Objectives: Females of reproductive age are increasingly using attention deficit hyperactivity disorder (ADHD) medication, but its use during pregnancy and breastfeeding is largely unknown. The aim of this study is to examine the prevalence of ADHD medication fills during pregnancy and breastfeeding, including characteristics of these females and cohort differences over time., Methods: We conducted a descriptive study using Danish nationwide registers. Within cohorts of pregnant and breastfeeding females, we calculated the prevalence of ADHD medication (methylphenidate, amphetamine, dexamfetamine, lisdexamfetamine, modafinil, atomoxetine, clonidine and guanfacine) fills and described sociodemographic and clinical characteristics across groups with fills, no fills and previous fills. Cohort differences in ADHD medication fills during pregnancy for 2005-2010, 2011-2016 and 2017-2022 were examined., Results: In this cohort of 1,077,279 pregnancies, ADHD medication fills increased from 0.08 to 7.71 per 1000 individuals between 2005 and 2022. Among 446,485 breastfeeding females, fills increased from 0.55 to 3.67 per 1000 individuals from 2012 to 2022. Compared with the group with no fills, females filling ADHD medication during pregnancy and breastfeeding were younger, had lower levels of education, were more often smoking during pregnancy, utilised more psychiatric healthcare and had concurrent fills of other psychotropic medication. Cohort differences over time revealed that females filling ADHD medication during pregnancy in 2017-2022 were older, had higher levels of education, smoked less during pregnancy, had fewer psychiatric contacts and were less likely to fill other psychotropic medications compared with females in the earlier cohorts., Conclusions: Results showed an increasing prevalence of ADHD medication fills during pregnancy and breastfeeding in Denmark over time, surpassing the increase observed generally in females of reproductive age filling ADHD medication. Results revealed a difference in characteristics of females filling ADHD medication during pregnancy over time, suggesting a shift in pregnancy treatment patterns., Competing Interests: Declarations. Funding: Open access funding provided by Aarhus Universitet. This study was funded by Sygeforsikring ‘danmark’ (journalnr. 2021–0139). Partial financial support was also received from the National Institute of Mental Health (NIMH) (R01MH122869). The funding agency had no role in the design, data analyses, interpretation of results, writing the article or decision to submit the article for publication. Conflict of interest: H.L. reports receiving grants from Shire Pharmaceuticals; personal fees from and serving as a speaker for Medice, Shire/Takeda Pharmaceuticals and Evolan Pharma AB; and sponsorship for a conference on attention-deficit/hyperactivity disorder from Shire/Takeda Pharmaceuticals and Evolan Pharma AB, all outside the submitted work. H.L. is editor-in-chief of JCPP Advances. T.M.O. has received a speaker's fee from Lundbeck A/S within the last 3 years. S.K.S. has received speaker’s honoraria from Takeda, Medice Arzneitmittel Pütter GmbH and Co KG as well as Janssen in the past 3 years. K.B.M. has received a speaker’s fee from Medice Nordic within the last 3 years. All other authors have nothing to declare. Ethics approval: The study was approved by the Danish Data Protection Agency and Statistics Denmark’s Scientific Board. Approval from the Ethics Committee was not required. All data have been deidentified and is not recognisable at an individual level. Consent to participate: Informed consent is not required for register-based studies according to Danish law. Consent for publication: Not applicable. Availability of data and materials: Access to individual-level data from Denmark is governed by Danish authorities. These include the Danish Data Protection Agency, the Danish Health Data Authority, the Ethical Committee and Statistics Denmark. Each scientific project must be approved before initiation, and approval is granted to a specific Danish research institution. Researchers at Danish research institutions may obtain the relevant approval to access data. International researchers may gain data access if governed by a Danish research institution having approval and data access. Code can be made available upon reasonable request. Authors’ contributions: M.G.M. and K.B.M. designed the study. M.G.M. analysed and wrote the first draft of the manuscript. J.Z. was responsible for data management and assisted with the analyses. K.B.M. assisted with and supervised all aspects of the article. All authors read and approved the final manuscript and agree to be accountable for the work., (© 2025. The Author(s).)

Background: Even though the development of an emotional bond to the child involves both parents, studies on the development of paternal bonding and the influencing factors are scarce. This pilot study examines the quality of paternal postnatal bonding in association with paternal depressive and anxiety symptoms before and after birth. Methods: Expecting parents ( n  = 81) were recruited from maternity services in Frankfurt, Germany. At recruitment and 3 months postpartum (pp) mothers and fathers completed an interview including sociodemographic and pregnancy data. Depressive and anxiety symptoms were screened using the Edinburgh Postnatal Depression Scale and the State-Trait Anxiety Inventory. At 3-month pp, fathers also completed the Postpartum Bonding Questionnaire for the assessment of bonding difficulties. A total of 63 couples, from whom data were available for both time points, were included in the final study group., Results: Depressive and anxiety symptoms before birth are the best predictors for the quality of paternal bonding pp (Total score R 2 .402 p  = .001; Impaired bonding R 2 .299 p  = .019; Rejection and Anger R 2 .353 p  = .005; Anxiety about care R 2 .457 p  = .000). Maternal depression and sociodemographic variables were not significantly associated., Limitations: High selected small study group., Conclusions: Paternal depressive and anxiety symptoms during pregnancy are highly predictive for the quality of bonding as well as for the presence of depressive and anxiety symptoms 3 month pp. It is necessary to identify these symptoms as soon as possible in order to prevent later negative impacts on parental mental health and on child developmental outcomes.

Social connectedness (SC) is one of the most important predictors for physical and mental health. Consequently, SC is addressed in an increasing number of studies, providing evidence for the multidimensionality of the construct, and revealing several factors that contribute to individual differences in SC. However, a unified model that can address SC subcomponents is yet missing. Here we take a novel perspective and discuss whether individual differences in SC can be explained by a person's social information processing profile that represents individual tendencies of how social information is perceived and interpreted and leads to motivated social behavior. After summarizing the current knowledge on SC and core findings from the fields of social perception and mentalizing, social motivation and social action, we derive a working model that links individual stages of social information processing to structural, functional, and qualitative aspects of SC. This model allows for deriving testable hypotheses on the foundations of SC and we outline several suggestions how these aspects can be addressed by future research., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Perinatal depression affects 10-15% of mothers and approximately 5% of fathers. However, only a small number of affected individuals seek treatment. If left unrecognized and untreated, it can have negative long-term consequences for the family's health, leading to subsequent high costs. Early treatment is crucial, yet there is a notable underdiagnosis and undertreatment. Affected individuals are often seen during this time, e.g. in paediatric practices, but not by specialists in mental health. Consequently, this study aims to increase detection and treatment rates of affected individuals by implementing a screening for depression and psychosocial stress in perinatal and postpartum parents within routine obstetric and paediatric care with subsequent advice and-if necessary-further referral to a mental health specialist., Methods: UPlusE is a prospective, cluster-randomized controlled trial conducted in an outpatient setting. Obstetric and paediatric practices will be randomized into an intervention and control group (1:1 ratio). Practices and enrolling patients will be required to use specific smartphone apps (practice apps) for interaction. The screening will occur with the apps at each paediatric checkup up to the child's age of 12 months, using the Edinburgh Postnatal Depression Scale (EPDS), KID-PROTEKT questionnaire, and the scale 1 (impaired bonding) of the Postpartum Bonding Questionnaire (PBQ-1). The goal is to screen 10,000 patients across Germany. Gynaecologists and paediatricians will receive certified training on peripartum depression. Participants in the intervention group with scores above cut-offs (EPDS ≥ 10, KID-PROTEKT ≥ 1, PBQ-1 ≥ 12) will receive counselling through their treating gynaecologists/paediatricians and will be provided with regional addresses for psychiatrists, psychotherapists, and "Frühe Hilfen" (early prevention) as well as family counselling centres, depending on symptom severity. At each screening, participants will be asked whether they sought support, where, and with whom (utilization). Utilization is the primary outcome., Discussion: The screening is designed to reduce underdiagnosis to enable suitable support at an early stage (especially for those often overlooked, such as individuals with "high-functioning depression") and hence to avoid manifestation of mental health problems in the whole family, especially infants who are exceptionally dependent on their parents and their well-being will benefit from this program., Trial Registration: German Clinical Trials Register, DRKS00033385. Registered on 15 January 2024., Competing Interests: Declarations Ethics approval and consent to participate {24} An ethics vote was obtained from the Ethics Committee at University Medicine Greifswald, (BB 120/23 dated 08.08.2023). All participants will be thoroughly informed through the practice app and can access the patient information at any time. They will provide their consent within the practice app, which they can review at any time. The consent is unequivocally attributable to the participating individual. Consent for publication {32} No images or videos relating to individual persons will be gained. Hence, a consent for publication is not applicable. Competing interests {28} SKS is the PI of the Babylotsen project and study in Würzburg, which is funded by Deutsches Hilfswerk, Stiftung SeeYou, and Lion’s Club Würzburg. This is a similar screening project but only screening patients and guiding them to the suitable support services within the Department of Gynaecology and Obstetrics at the University Hospital Würzburg. All the other authors declare that they have no competing interests., (© 2024. The Author(s).)

Adult ADHD is associated with increased risk for suicide attempts, as indicated by investigations of population- and community-based cohorts. However, there is little data regarding suicide attempts in a clinical setting. To address this, we used a comprehensively phenotyped clinical adult ADHD (aADHD) cohort to assess to which extent comorbidity, psychosocial adversity, personality, and ADHD symptoms contribute to suicidal behavior in ADHD. Furthermore, we investigated a triallelic variation in the serotonin transporter-linked polymorphic region (5-HTTLPR), which has previously been associated with suicidal behavior. Depression, substance use, eating, and posttraumatic stress disorders were independently associated with past suicide attempts, whereas anxiety, somatoform, and obsessive-compulsive spectrum disorders showed no association. Pulmonary diseases also showed an association with suicidal behavior. Psychosocial factors including occupational status, marital status/living situation, externalizing behavior and psychiatric family history were strongly associated with past suicide attempts. ADHD symptoms of inattention and hyperactivity/impulsivity were not associated with past suicide attempts after adjustment for psychiatric comorbidity and psychosocial adversity. However, the personality trait of neuroticism fully mediated the association between depression and suicidal behavior. 5-HTTLPR was not associated with suicidal behavior, but an interaction with ADHD symptoms and subtype was found. Our data suggest that psychiatric comorbidity and psychosocial adversity are key factors for suicidal behavior in aADHD, with neuroticism representing a critical mediator of the association between depression and suicidality. Further research, preferentially with longitudinal study designs is needed to better understand causal factors for suicidal behavior to enable effective preventive action., (© 2024. The Author(s).)

Perinatal mental health care differs around the world. We provide a global perspective on the current status of service provision, barriers and facilitators to access, and strategies to improve access in high-income and low- and middle-income countries across five continents (Asia, Africa, Europe, North America and South America). Many of the countries considered do not have universal healthcare coverage. This poses a challenge to perinatal mental health care access. However, there are other social and structural barriers to access, including stigma and other sources of marginalization and discrimination. Yet there are opportunities discussed herein to learn more about what perinatal mental health services work for what populations* and in what circumstances, by adopting a global lens to examine innovative solutions utilized across geographical settings., Competing Interests: Disclosures NB has received salary and/or funding support from Massachusetts Department of Mental Health via the Massachusetts Child Psychiatry Access Program for Moms (MCPAP for Moms). She is also the Medical Director of Research and Evaluation for MCPAP for Moms and the Executive Director of the Lifeline for Families Center at UMass Chan Medical School. She has served as a consultant for The Kinetix Group, VentureWell, and JBS International. SKS received speaker`s and author's honoraria from Takeda, Medice and Janssen. No other conflicts of interest to disclose by authors., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to investigate the effects of the COVID-19 pandemic on maternal mental health during pregnancy and the postpartum period., Methods: The impact of the COVID-19 pandemic situation during and post pregnancy was addressed on three main factors; maternal mental health, mother-child bonding, and maternal self-confidence. To do this, two different patient cohorts were compared; data from one cohort was collected pre-pandemic, and data was collected from the other cohort at the beginning of the pandemic. Questionnaires were used to collect data regarding depressive symptoms (Edinburgh Postnatal Depression Scale [EPDS]), anxiety (State Trait Anxiety Inventory [STAI]), maternal self-confidence (Lips Maternal Self-Confidence Scale [LMSCS]) and mother-child bonding (Postpartum Bonding Questionnaire [PBQ])., Results: There were no significant differences in depressive symptoms (EPDS with an average median of 4.00-5.00) or anxiety (STAI with an average median of 29.00-33.00) between the cohorts. However, the quality of postpartum maternal bonding was higher at 3-6 months in the pandemic cohort, which was also influenced by education and the mode and number of births. The maternal self-confidence was lower in the pandemic sample, also depending on the mode of birth delivery., Conclusions: In this study, a differential effect of the COVID-19 pandemic on mother-child bonding and maternal self-confidence was observed. The results thereby identified possible protective factors of the pandemic, which could potentially be implemented to improve maternal mental health and bonding to the child under normal circumstances., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bartmann et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 17 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of genes involved in neurotransmission and neurodevelopment including SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, CRTC3, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, DPH1, GSDMB, MED24 and THRA in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance of BD polygenic risk scores across diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI)., Competing Interests: Competing interests OAA has served as a speaker for Janssen, Lundbeck, and Sunovion and as a consultant for Cortechs.ai. SKS has served as speaker for Janssen, Takeda and Medice Arzneimittel Puetter GmbH & CoKG. EV has received grants and served as consultant, advisor or CME speaker for the following entities (unrelated to the present work): AB-Biotics, Abbott, Abbvie, Adamed, Angelini, Biogen, Biohaven, Boehringer Ingelheim, Casen-Recordati, Celon, Compass, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research, Glaxo Smith-Kline, Idorsia, Janssen, Johnson & Johnson, Lundbeck, Newron, Novartis, Organon, Otsuka, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris. PBM has received remuneration from Janssen (Australia) and Sanofi (Hangzhou) for lectures, and Janssen (Australia) for advisory board membership. MOD and MJO have received grants from Akrivia Health and Takeda Pharmaceuticals for work unrelated to this project.

Purpose: To examine the association between partner support for women's antidepressant treatment and depressive symptoms in pregnant women, those planning pregnancy, and mothers who ever used antidepressants., Methods: We included 334 women (n=44 planners, n=182 pregnant, n=108 mothers) ever treated with antidepressants within the HEALTHx2 study, a web-based cross-sectional study conducted across Norway in June 2020 to June 2021. The Edinburgh Postnatal Depression Scale and two questions of the Patient Health Questionnaire measured depressive symptoms, by degree of severity and for depressed mood, anxiety, and anhedonia sub-dimensions. Partner support was measured using one item from the Antidepressant Compliance Questionnaire. Association was estimated via unadjusted and adjusted linear and logistic regression models., Results: Being unsupported by the partner was associated with increased odds of reporting moderate-to-very-severe depressive symptoms in mothers (adjusted odds ratio (aOR), 3.57; 95% confidence interval (CI), 1.04-12.19) and pregnant women (aOR, 3.26; 95% CI, 0.95-11.14), relative to being supported. Pregnant women (adjusted mean difference (β), 0.76; 95% CI, 0.14-1.38) and mothers (β, 0.93; 95% CI, 0.23-1.64) with no support for their antidepressant treatment presented greater symptoms of anhedonia; for women planning pregnancy, this association emerged in relation to anxiety symptoms (β among non-users of antidepressant, 2.58; 95% CI, 1.04-4.13)., Conclusions: Partner support for women's antidepressant treatment may play a key role in depressive symptoms severity and the subtypes of anhedonia and anxiety, among women planning pregnancy, pregnant women, and mothers. This highlights the importance of partner inclusion in the complex decision-making process for antidepressant treatment around the time of pregnancy., (© 2024. The Author(s).)

Objective: Increasing evidence suggests that the physiological changes of pregnancy may impact pharmacokinetics of antiseizure medications (ASM), and this may affect treatment outcomes. The aim of this study was to quantify the pregnancy impact on the ASM pharmacokinetics., Methods: A systematic literature search was conducted in PubMed/EMBASE in November 2022 and updated in August 2023 for studies comparing levels of ASM in the same individuals during pregnancy and in the preconception/postpartum period. Alteration ratios between the 3rd trimester and baseline were estimated. We also performed a random-effects meta-analysis calculating between-timepoint differences in mean differences (MDs) and 95% confidence intervals (95%CIs) for dose-adjusted plasma concentrations (C/D ratios). Study quality was assessed using the ClinPK guidelines., Results: A total of 65 studies investigating 15 ASMs in 674 pregnancies were included. The largest differences were reported for lamotrigine, oxcarbazepine and levetiracetam (alteration ratio 0.42, range 0.07-2.45, 0.42, range 0.08-0.82 and 0.52, range 0.04-2.77 respectively): accordingly, C/D levels were lower in the 3rd trimester for lamotrigine, levetiracetam and the main oxcarbazepine metabolite monohydroxycarbazepine (MD = -12.33 × 10 -3 , 95%CI = -16.08 to -8.58 × 10 -3 (μg/mL)/(mg/day), p < 0.001, MD = -7.16 (μg/mL)/(mg/day), 95%CI = -9.96 to -4.36, p < 0.001, and MD = -4.87 (μg/mL)/(mg/day), 95%CI = -9.39 to -0.35, p = 0.035, respectively), but not for oxcarbazepine (MD = 1.16 × 10 -3 (μg/mL)/(mg/day), 95%CI = -2.55 to 0.24 × 10 -3 , p = 0.10). The quality of studies was acceptable with an average rating score of 11.5., Conclusions: Data for lamotrigine, oxcarbazepine (and monohydroxycarbazepine) and levetiracetam demonstrate major changes in pharmacokinetics during pregnancy, suggesting the importance of therapeutic drug monitoring to assist clinicians in optimizing treatment outcomes., Competing Interests: Declaration of competing interest Dr. Deligiannidis reported grants from the National Institutes of Health (Grant R01MH120313) during the conduct of study, nonfinancial support and personal fees from Sage Therapeutics Inc. (i.e., travel reimbursement, consulting), and Brii Biosciences (i.e., consulting); Dr. Kittel-Schneider has received speaker's and author's fee from Medice Arzneimittel Pütter GmbH & Co KG and Takeda; Dr. Paulzen has received speaker fees from Neuraxpharm, Langenfeld, Germany, and Lundbeck, Hamburg, Germany; Dr. Schoretsanitis has served as a consultant for Dexcel Pharma, HLS Therapeutics, Saladax and Thermo Fisher and has received speaker fees from HLS Therapeutics and Saladax; All other authors declare no conflicts of interest. The research study did not receive funds or support from any source., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II., Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism., Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II., (© 2024. The Author(s).)

Background: Motor alterations and lowered physical activity are common in affective disorders. Previous research has indicated a link between depressive symptoms and declining muscle strength primarily focusing on the elderly but not younger individuals. Thus, we aimed to evaluate the relationship between mood and muscle strength in a sample of N = 73 young to middle-aged hospitalized patients (18-49 years, mean age 30.7 years) diagnosed with major depressive, bipolar and schizoaffective disorder, with a focus on moderating effects of psychopharmacotherapy. The study was carried out as a prospective observational study at a German psychiatric university hospital between September 2021 and March 2022., Methods: Employing a standardized strength circuit consisting of computerized strength training devices, we measured the maximal muscle strength (F max ) using three repetitions maximum across four muscle regions (abdomen, arm, back, leg) at three time points (t 1 -t 3 ) over four weeks accompanied by psychometric testing (MADRS, BPRS, YRMS) and blood lipid profiling in a clinical setting. For analysis of psychopharmacotherapy, medication was split into activating (AM) and inhibiting (IM) medication and dosages were normalized by the respective WHO defined daily dose., Results: While we observed a significant decrease of the MADRS score and increase of the relative total F max (rTF max ) in the first two weeks (t 1 -t 2 ) but not later (both p < .001), we did not reveal a significant bivariate correlation between disease severity (MADRS) and muscle strength (rTF max ) at any of the timepoints. Individuals with longer disease history displayed reduced rTF max (p = .048). IM was significantly associated with decreased rTF max (p = .032). Regression models provide a more substantial effect of gender, age, and IM on muscle strength than the depressive episode itself (p < .001)., Conclusions: The results of the study indicate that disease severity and muscle strength are not associated in young to middle-aged inpatients with affective disorders using a strength circuit as observational measurement. Future research will be needed to differentiate the effect of medication, gender, and age on muscle strength and to develop interventions for prevention of muscle weakness, especially in younger patients with chronic affective illnesses., (© 2024. The Author(s).)

Background: The escalating prescription of psychopharmacological medications to women of reproductive age underscores the growing significance of sex-specific variations in pharmacotherapy. Despite this, clinical trials have largely overlooked these differences. Preliminary data indicate sex-specific variations in the neurobiology of affective disorders and in the metabolism, pharmacodynamics, and kinetics of therapeutic drugs. This underscores the imperative for a more nuanced exploration of menstrual cycle-dependent fluctuations in psychotropic drugs. This pilot study aimed to investigate drug and hormone fluctuations in female patients with affective disorders, aiming to enhance comprehension of the interplay between cycle-related hormone fluctuations and pharmacokinetics. The ultimate goal is to facilitate more effective and safer pharmacological therapy in the future., Methods: Blood samples were collected from 27 patients and 27 age-matched control participants at 3 distinct time points (early follicular phase, ovulation, and late luteal phase) during each menstrual cycle. Depressive and manic symptoms were assessed, and hormone concentrations were measured in the entire sample, while drug concentrations were assessed solely in the affective disorder sample using mass spectrometry., Results: Significant variations in drug concentration were observed throughout the menstrual cycle for bupropion, with a trend toward altered concentration for venlafaxine. Moreover, notable differences in hormone concentrations were identified between patients and controls, even after accounting for the impact of contraceptive use, diagnoses, and medication., Conclusions: This pilot study reinforces previously reported data, underscoring the significance of sex-specific pharmacological therapy approaches. It provides further evidence supporting the interaction among sex hormones, drugs, and symptoms of affective disorders., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations., Methods: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data., Results: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers., Conclusions: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD., (© 2024. The Author(s).)

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD., (© 2024. The Author(s).)

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation treatment used as an alternative or complementary treatment for various neuropsychiatric disorders, and could be an alternative or add-on therapy to psychostimulants in attention-deficit hyperactivity disorder (ADHD). Previous studies provided some evidence for improvements in cognition and clinical symptoms in pediatric and adult ADHD patients. However, data from multi-center randomized controlled trials (RCTs) for this condition are lacking. Thus, our aim is to evaluate short- and mid-term effects of tDCS in this multi-center, randomized, double blind, and sham-controlled, parallel group clinical trial with a 1:1 randomization ratio. Primary endpoint is the total score of DSM-IV scale of the internationally established Conners' Adult ADHD Rating Scales (German self-report screening version, CAARS-S-SR), at day 14 post-intervention (p.i.) to detect short-term lasting effects analyzed via analyses of covariance (ANCOVAs). In case of significant between-groups differences at day 14 p.i., hierarchically ordered hypotheses on mid-term lasting effects will be investigated by linear mixed models with visit (5 time points), treatment, treatment by visit interaction, and covariates as fixed categorical effects plus a patient-specific visit random effect, using an unstructured covariance structure to model the residual within-patient errors. Positive results of this clinical trial will expand the treatment options for adult ADHD patients with tDCS and provide an alternative or add-on therapy to psychostimulants with a low risk for side effects.Trial Registration The trial was registered on July 29, 2022 in the German Clinical Trials Register (DRKS00028148)., (© 2023. The Author(s).)

Introduction: The role of emotional dysregulation (ED) in attention-deficit/hyperactivity disorder (ADHD) has become an important issue. This study, in which we analyzed data from a predictive pharmaco-EEG-trial, aimed to examine whether symptoms of ED in adult ADHD affect ADHD symptom severity, brain arousal regulation as measured by resting EEG, and the response to stimulant medication., Methods: ED is defined as having a sex- and age-corrected T -score of >70 on the emotional lability subscale of the German version of Conners' Adult ADHD Rating Scale. A total of 115 participants were included in the study, 56 of whom had ED. Participants with ED were more impaired in terms of the severity of core ADHD symptoms, especially inattentive symptoms, comorbid depressive symptoms, interpersonal relationships, and quality of life. In addition, participants with ED were more likely to report a total score above 13 on the Beck Depression Inventory-II, which was considered to be the cutoff for mild depression., Results: No differences were found between the ED and non-ED groups in response to stimulant medication or in brain arousal regulation. In addition, there was no significant effect of ED with comorbid depressive symptoms on treatment response. There was a trend for subgroups that showed a change in brain arousal regulation associated with symptom improvement., Discussion: Our findings may support the assumption that ED may be an important feature of ADHD. The use of EEG-based brain arousal regulation as a diagnostic and predictive tool in ADHD in the presence of ED and comorbid depressive symptoms should be further investigated., Competing Interests: MS has received speaker’s fees from MEDICE Arzneimittel Pütter GmbH & Co. KG and Takeda and was an advisory board member for Takeda in the past 3 years. AR has received honoraria for advisory boards or talks from MEDICE Arzneimittel Pütter GmbH & Co. KG, Takeda, Janssen, Boehringer Ingelheim, SAGE/Biogen, cyclerion, COMPASS and LivaNova. JG has received research funding from the German Federal Ministry of Education and Research, German Science Foundation, and speaker fees from Lundbeck, Janssen-Cilag, Lilly, and Boehringer. SK-S. has received author’s and speaker’s honoraria from Takeda and Medice Arzneimittel Pütter GmbH &Co. KG in the past 3 years. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Huang, Mauche, Ahlers, Bogatsch, Böhme, Ethofer, Fallgatter, Gallinat, Hegerl, Heuser, Hoffmann, Kittel-Schneider, Reif, Schöttle, Unterecker and Strauß.)

Early identification and intervention of individuals with an increased risk for bipolar disorder (BD) may improve the course of illness and prevent long‑term consequences. Early-BipoLife, a multicenter, prospective, naturalistic study, examined risk factors of BD beyond family history in participants aged 15-35 years. At baseline, positively screened help-seeking participants (screenBD at-risk) were recruited at Early Detection Centers and in- and outpatient depression and attention-deficit/hyperactivity disorder (ADHD) settings, references (Ref) drawn from a representative cohort. Participants reported sociodemographics and medical history and were repeatedly examined regarding psychopathology and the course of risk factors. N = 1,083 screenBD at-risk and n = 172 Ref were eligible for baseline assessment. Within the first two years, n = 31 screenBD at-risk (2.9 %) and none of Ref developed a manifest BD. The cumulative transition risk was 0.0028 at the end of multistep assessment, 0.0169 at 12 and 0.0317 at 24 months (p = 0.021). The transition rate with a BD family history was 6.0 %, 4.7 % in the Early Phase Inventory for bipolar disorders (EPIbipolar), 6.6 % in the Bipolar Prodrome Interview and Symptom Scale-Prospective (BPSS-FP) and 3.2 % with extended Bipolar At-Risk - BARS criteria). In comparison to help-seeking young patients from psychosis detection services, transition rates in screenBD at-risk participants were lower. The findings of Early-BipoLife underscore the importance of considering risk factors beyond family history in order to improved early detection and interventions to prevent/ameliorate related impairment in the course of BD. Large long-term cohort studies are crucial to understand the developmental pathways and long-term course of BD, especially in people at- risk., Competing Interests: Declaration of Competing Interest JM, KLB, CB, KL, CS, JM, GJ, AJF, ML, AB, AR, SM, TS, TK, IF, AJ, UD, SKÖ, PFP, LMH, PR, SB, PM, BM and AP state to have no conflict of interest. SKS has received author's and advisory honoraria from Takeda/Shire and Medice Arzneimittel Pütter GmbH in the last 3 years. AR serves on advisory boards and receives speaker's honoraria from Medice, Shire/Takeda, Janssen, neuraxpharm, Servier and SAGE. MB has received grant support from the Deutsche Forschungsgemeinschaft, the Bundesministerium für Bildung und Forschung, and the European Commission. He served as a consultant to GH Research, Janssen-Cilag, neuraxpharm, Novartis, Shire International, Sunovion, and Takeda, and received fees from Aristo, Hexal, Janssen-Cilag, and Sunovion. CU Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantic., (Copyright © 2023. Published by Elsevier B.V.)

Understanding the interrelationship between the gut microbiota and host physiology, although still in its relative infancy, has taken important steps forward over the past decade. In the context of brain disorders including those characterized by neurodevelopmental and neurodegenerative changes there have been important advances. However, initially research involved correlational analyses, had limited translational scope, and lacked functional assessments. Thus, largescale longitudinal clinical investigations that assess causation and underlying mechanisms via in depth analysis methods are needed. In neurodegeneration research, strong causal evidence now links the gut microbiome to Alzheimer's (AD), and Parkinson's Disease (PD), as supported by human-to-animal transplantation studies. Longitudinal interventions are being conducted in AD, PD, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Neurodevelopmental research has also seen a boon in microbiome-related clinical research including in autism, Attention-deficit/hyperactivity disorder, and schizophrenia, which is confirming prior animal model work regarding the key time-windows in the gut microbiome important for infant cognition. While recent research advances represent important progress, fundamental knowledge gaps and obstacles remain. Knowing how and why the gut microbiome changes at the extremes of life will develop our mechanistic understanding and help build the evidence base as we strive toward counteracting microbial missteps with precision therapeutic interventions.

Anxious depression represents a subtype of major depressive disorder and is associated with increased suicidality, severity, chronicity and lower treatment response. Only a few studies have investigated the differences between anxious depressed (aMDD) and non-anxious depressed (naMDD) patients regarding treatment dosage, serum-concentration and drug-specific treatment response. In our naturalistic and prospective study, we investigated whether the effectiveness of therapy including antidepressants (SSRI, SNRI, NaSSA, tricyclics and combinations) in aMDD patients differs significantly from that in naMDD patients. In a sample of 346 patients, we calculated the anxiety somatization factor (ASF) and defined treatment response as a reduction (≥50%) in the Hamilton Depression Rating Scale (HDRS)-21 score after 7 weeks of pharmacological treatment. We did not observe an association between therapy response and the baseline ASF-scores, or differences in therapy outcomes between aMDD and naMDD patients. However, non-responders had higher ASF-scores, and at week 7 aMDD patients displayed a worse therapy outcome than naMDD patients. In subgroup analyses for different antidepressant drugs, venlafaxine-treated aMDD patients showed a significantly worse outcome at week 7. Future prospective, randomized-controlled studies should address the question of a worse therapy outcome in aMDD patients for different psychopharmaceuticals individually.

Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II., Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism., Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II., Competing Interests: Competing interests Eduard Vieta has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbvie, Almirall, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, GH Research, Glaxo-Smith-Kline, Janssen, Lundbeck, Orion, Otsuka, Pfizer, Roche, Rovi, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), the Stanley Medical Research Institute and Viatris. Michael Bauer has received grants from the Deutsche Forschungsgemeinschaft (DFG), and Bundesministeriums für Bildung und Forschung (BMBF), and served as consultant, advisor or CME speaker for the following entities: Allergan, Aristo, Janssen, Lilly, Lundbeck, neuraxpharm, Otsuka, Sandoz, Servier and Sunovion outside the submitted work. Sarah Kittel-Schneider has received grants and served as consultant, advisor or speaker for the following entities: Medice Arzneimittel Pütter GmbH and Takeda. Bernhard Baune has received grants and served as consultant, advisor or CME speaker for the following entities: AstraZeneca, Bristol-Myers Squibb, Janssen, Lundbeck, Otsuka, Servier, the National Health and Medical Research Council, the Fay Fuller Foundation, the James and Diana Ramsay Foundation. Tadafumi Kato received honoraria for lectures, manuscripts, and/or consultancy, from Kyowa Hakko Kirin Co, Ltd, Eli Lilly Japan K.K., Otsuka Pharmaceutical Co, Ltd, GlaxoSmithKline K.K., Taisho Toyama Pharmaceutical Co, Ltd, Dainippon Sumitomo Pharma Co, Ltd, Meiji Seika Pharma Co, Ltd, Pfizer Japan Inc., Mochida Pharmaceutical Co, Ltd, Shionogi & Co, Ltd, Janssen Pharmaceutical K.K., Janssen Asia Pacific, Yoshitomiyakuhin, Astellas Pharma Inc, Wako Pure Chemical Industries, Ltd, Wiley Publishing Japan, Nippon Boehringer Ingelheim Co Ltd, Kanae Foundation for the Promotion of Medical Science, MSD K.K., Kyowa Pharmaceutical Industry Co, Ltd and Takeda Pharmaceutical Co, Ltd. Tadafumi Kato also received a research grant from Takeda Pharmaceutical Co, Ltd. Peter Falkai has received grants and served as consultant, advisor or CME speaker for the following entities Abbott, GlaxoSmithKline, Janssen, Essex, Lundbeck, Otsuka, Gedeon Richter, Servier and Takeda as well as the German Ministry of Science and the German Ministry of Health. Eva Reininghaus has received grants and served as consultant, advisor or CME speaker for the following entities: Janssen and Institut Allergosan. Mikael Landén has received lecture honoraria from Lundbeck. Kazufumi Akiyama has received consulting honoraria from Taisho Toyama Pharmaceutical Co, Ltd. Scott Clark has received grants, or data and served as consultant, advisor or CME speaker for the following entities: Otsuka Austalia, Lundbeck Australia, Janssen-Cilag Australia, Servier Australia,Viatris. Bruno Etain received honoraria from Sanofi Aventis. The rest of authors have no conflicts of interest to disclose.

Competing Interests: Conflict of interest SKS is member of the international and German speaking Marcé-Society as well as of the EU COST Action RiseupPPD. NC has no conflict of interest to declare.

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li + ) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li PGS ) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li + PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi + Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li + PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li + PGS was positively associated with lithium treatment response in the ConLi + Gen cohort, in both the categorical (P = 9.8 × 10 - 12 , R 2  = 1.9%) and continuous (P = 6.4 × 10 - 9 , R 2  = 2.6%) outcomes. Compared to bipolar patients in the 1 st decile of the risk distribution, individuals in the 10 th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10 - 4 , R 2  = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li + PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment., (© 2023. The Author(s).)

Non-suicidal self-injury (NSSI) during adolescence is a high-risk marker for the development and persistence of mental health problems and has been recognized as a significant public health problem. Whereas targeted prevention has indeed shown to be effective in reducing NSSI and improve mental health problems, access to such programs is limited. By face validity, universal prevention of NSSI seems an ideal starting point for a stepped-care model to circumvent a lack of resources in the medical care system. However, it is yet unclear how effective such approaches are. Here, we provide a summary of existing work on universal prevention of NSSI in adolescents younger than 21 years based on a systematic literature search. We found that only seven studies are available. None of the programs evaluated was found to be effective in reducing the incidence or frequency of NSSI. After providing a comprehensive summary of the existing work, we evaluate the fact that existing work primarily focusses on selected/targeted prevention and on psychoeducational methods. We derive implications for future directions in the field of universal prevention of NSSI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bürger, von Schoenfeld, Scheiner, Seidel, Wasserscheid, Gad, Kittel-Schneider, Romanos and Reiter.)

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2,039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD., Competing Interests: MAd has received a grant from Servier, speaker’s fees from Servier, Lundbeck, Aristo, Parexel, Gilead, ViiV, Deutsche Bank, MSD, and MyTomorrows, plus a non-financial support from Lundbeck. KA has received speaker’s fees from Taisho Toyama Pharmaceutical. MAl is funded by a grant of the Canadian Institutes of Health Research. MB has received speaker’s fees from AstraZeneca, Pfizer, Lilly, Lundbeck, GlaxoSmithKline, Servier, and Ferrer Internacional. BÉ received non-financial support from Labex Biopsy and Fondation Fondamental. RH received grants and speaker honoraria from Dainippon Sumitomo Pharma and Novartis plus speaker honoraria from Eli Lilly Japan, GlaxoSmithKline, Hisamitsu Pharmaceutical, Janssen Pharmaceutical, Nippon Zoki Pharmaceutical, Otsuka Pharmaceutical, Astellas Pharma, Pfizer, and the Yoshitomiyakuhin Corporation. TK received a grant from Takeda Pharmaceutical and fees from Kyowa Hakko Kirin, Eli Lilly Japan, Otsuka Pharmaceutical, GlaxoSmithKline, Taisho Toyama Pharmaceutical, Dainippon Sumitomo Pharma, Meiji Seika Pharma, PfizerJapan, Mochida Pharmaceutical, Shionogi & Co, Janssen Pharmaceutical, Yoshitomiyakuhin Corporation, Agilent Technologies, Astellas Pharma, and Wako Pure Chemical Industries. IK received grants and fees from Dainippon Sumitomo Pharma, Eisai, Eli Lilly, GlaxoSmithKline, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Novartis, Otsuka, Ono Pharmaceutical, Pfizer, Tanabe Mitsubishi Pharma, Takeda Pharmaceutical, Shionogi, and Yoshitomi Pharmaceutical; he received grants from AbbVie GK, Asahi Kasei Pharma, Boehringer Ingelheim, Chugai Pharmaceutical, and Daiichi Sankyo and fees from Astellas Pharma and Janssen Pharmaceutical. MJM served as unpaid consultant for Pathway Genomic (San Diego, USA). SLM received a grant and fees from Naurex and Shire, further grants from Alkermes, Cephalon, Forest, Marriott Foundation, Orexigen Therapeutics, and Takeda Pharmaceutical, he further has served on the advisory boards for Bracket, Hoffmann-La Roche, MedAvante, Sunovion and received fees from Novo Nordisk. RHP received personal fees from RID Ventures, Genomind LLC, Healthrageous, P zer, Perfect Health, Proteus, and Psybrain. PRS received a grant from NHMRC. TGS received a grant and fees from Roche Pharmaceuticals. TSt received personal fees from Servier, Lundbeck, and Bristol-Myers Squibb. MM has received grants from Lundbeck and Angelini. EV has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, AbbVie, Adamed, Angelini, Biogen, Biohaven, Boehringer-Ingelheim, Celon Pharma, Compass, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research, Glaxo-Smith Kline, HMNC, Idorsia, Janssen, Lundbeck, Medincell, Merck, Novartis, Orion Corporation, Organon, Otsuka, Roche, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris, outside the submitted work. SRC has participated in advisory and educational boards and received speaker’s fees from Janssen-Cilag, Lundbeck, Otsuka, and Servier; research funding from Janssen-Cilag, Lundbeck, Otsuka, and Gilead; and data sharing from Viatris Australia. ML has received lecture honoraria from Lundbeck pharmaceuticals. All above listed interests are outside of the submitted work. All other authors declare no competing interests.