Synaptic proteome perturbations after maternal immune activation: Identification of embryonic and adult hippocampal changes.

BACKGROUND: Maternal immune activation (MIA) triggers neurobiological changes in offspring, potentially reshaping the molecular synaptic landscape, with the hippocampus being particularly vulnerable. However, critical details regarding developmental timing of these changes and whether they differ between males and females remain unclear. METHODS: We induced MIA in C57BL/6J mice on gestational day nine using the viral mimetic poly(I:C) and performed mass spectrometry-based proteomic analyses on hippocampal synaptoneurosomes of embryonic (E18) and adult (20 ± 1 weeks) MIA offspring. RESULTS: In the embryonic synaptoneurosomes, MIA led to lipid, polysaccharide, and glycoprotein metabolism pathway disruptions. In the adult synaptic proteome, we observed a dynamic shift toward transmembrane trafficking, intracellular signalling cascades, including cell death and growth, and cytoskeletal organisation. In adults, many associated pathways overlapped between males and females. However, we found distinct sex-specific enrichment of dopaminergic and glutamatergic pathways. We identified 50 proteins altered by MIA in both embryonic and adult samples (28 with the same directionality), mainly involved in presynaptic structure and synaptic vesicle function. We probed human phenome-wide association study data in the cognitive and psychiatric domains, and 49 of the 50 genes encoding these proteins were significantly associated with the investigated phenotypes. CONCLUSIONS: Our data emphasise the dynamic effects of viral-like MIA on developing and mature hippocampi and provide novel targets for study following prenatal immune challenges. The 22 proteins that changed directionality from the embryonic to adult hippocampus, suggestive of compensatory over-adaptions, are particularly attractive for future investigations.

Safety and tolerability of esketamine nasal spray versus quetiapine extended release in patients with treatment resistant depression.

In ESCAPE-TRD (NCT04338321), esketamine nasal spray (NS) significantly increased the probability of remission at Week 8, and of being relapse-free through Week 32 after remission at Week 8, versus quetiapine extended release (XR) in patients with treatment resistant depression (TRD). Here, we explore the time course, burden and consequences of treatment emergent adverse events (TEAEs) in the phase IIIb ESCAPE­TRD trial. Patients with TRD were randomised 1:1 to esketamine NS or quetiapine XR, dosed per label alongside an ongoing selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor. In this secondary publication, safety analyses (comprising patients who received ≥1 dose of study treatment) included incidence, severity and durations (Kaplan­Meier method) of TEAEs, and subsequent dispositional changes. P values were not adjusted for multiple testing. 336 patients were randomised to esketamine NS and 340 to quetiapine XR; 334 and 336 received ≥1 dose of study treatment, respectively. TEAEs were significantly more common with esketamine NS than quetiapine XR (91.9 % versus 78.0 %; p < 0.001), but were typically mild/moderate and transient in nature: a greater proportion resolved on the same-day (92.0 % versus 12.1 %) and lead to treatment discontinuation in significantly fewer patients (4.2 % versus 11.0 %, respectively; p < 0.001). The proportion of days spent with TEAEs was significantly lower with esketamine NS than quetiapine XR (median: 11.9 % versus 21.3 %; p < 0.001). Although more frequent with esketamine NS, TEAEs were typically transient and mild, with discontinuation less likely versus quetiapine XR. Data were consistent with established safety profiles, with no new safety signals identified. Alongside greater efficacy, the demonstrably more favourable tolerability profile of esketamine NS versus quetiapine XR further supports its use for TRD.

When, Why and How to Re-challenge Clozapine in Schizophrenia Following Myocarditis.

Clozapine-induced myocarditis (CIM) is among the most important adverse events limiting the use of clozapine as the most effective treatment for schizophrenia. CIM necessitates the immediate termination of clozapine, often resulting in its permanent discontinuation with considerable detrimental effects on patients' psychopathology and long-term outcome. Consequently, a clozapine re-challenge after CIM is increasingly regarded as a viable alternative, with published reports indicating a success rate of approximately 60%. However, published cases of re-challenges after CIM remain limited. Here, we provide a narrative review of the current state of research regarding the epidemiology, pathophysiology, risk factors, diagnosis and clinical management of CIM as well as a synthesis of current recommendations for re-challenging patients after CIM. This includes a step-by-step guide for this crucial procedure based on the current evidence regarding the pathophysiology and risk factors for CIM. Slow dose titration regimes and addressing risk factors including concomitant valproate and olanzapine are crucial both to prevent CIM and to ensure a safe and successful re-challenge. Furthermore, we discuss the utility of C-reactive protein, troponin, N-terminal-pro hormone and brain natriuretic peptide, therapeutic drug-monitoring and cardiac magnetic resonance imaging for CIM screening and diagnosis as well as for post-CIM re-challenges.

Exploring weight-related self-monitoring as a potential risk factor for eating disorder symptoms in adults - A systematic review and meta-analysis.

OBJECTIVE: Weight-related self-monitoring (WRSM), which involves the intentional tracking of body weight metrics, has been considered a potential risk factor for eating disorders. Therefore, the aim of this study was to systematically summarize the current state of the literature and to quantify the possible association between WRSM and eating disorder symptoms in adults. METHOD: Preregistration was carried out using PROSPERO (ID CRD42022366133). The PubMed, PsycInfo, and Web of Science databases were searched until December 21, 2023. A study had to be 1) be available in English or German, 2) be peer-reviewed and quantitative, 3) include adult participants (age ≥18 years) from the general population, 4) assess eating disorder symptoms via at least one of the following questionnaires: EDI, EAT, FEV, TFEQ, DEBQ, EDE-Q, Munich ED-Quest or IEG, and 5) include WRSM. Data analyses included descriptive analyses and three-level meta-analysis, corrected for correlations, for the global score and the different subscales of the eating disorder questionnaires. RESULTS: A total of 28 studies (n = 17,370 participants), with an overall fair methodological quality, were included in the systematic review. Out of these studies, nine studies with n = 13,507 participants were ultimately analyzed in the meta-analysis. The three-level meta-analysis did not reveal a significant association between WRSM and the eating disorder global score (r = 0.13, 95% CI [-0.02, 0.28]; p = 0.08), with this pattern also being evident in the subgroup analysis (diet monitoring). DISCUSSION: WRSM alone does not generally translate into an increased risk of disordered eating symptoms in the general population. We assume that individual factors are likely to determine whether the use of WRSM could lead to eating disorder symptoms. These factors should be accounted for in future research.

Assessing the Accuracy of Smartwatch-Based Estimation of Maximum Oxygen Uptake Using the Apple Watch Series 7: Validation Study.

BACKGROUND: Determining maximum oxygen uptake (VO2max) is essential for evaluating cardiorespiratory fitness. While laboratory-based testing is considered the gold standard, sports watches or fitness trackers offer a convenient alternative. However, despite the high number of wrist-worn devices, there is a lack of scientific validation for VO2max estimation outside the laboratory setting. OBJECTIVE: This study aims to compare the Apple Watch Series 7's performance against the gold standard in VO2max estimation and Apple's validation findings. METHODS: A total of 19 participants (7 female and 12 male), aged 18 to 63 (mean 28.42, SD 11.43) years were included in the validation study. VO2max for all participants was determined in a controlled laboratory environment using a metabolic gas analyzer. Thereby, they completed a graded exercise test on a cycle ergometer until reaching subjective exhaustion. This value was then compared with the estimated VO2max value from the Apple Watch, which was calculated after wearing the watch for at least 2 consecutive days and measured directly after an outdoor running test. RESULTS: The measured VO2max (mean 45.88, SD 9.42 mL/kg/minute) in the laboratory setting was significantly higher than the predicted VO2max (mean 41.37, SD 6.5 mL/kg/minute) from the Apple Watch (t18=2.51; P=.01) with a medium effect size (Hedges g=0.53). The Bland-Altman analysis revealed a good overall agreement between both measurements. However, the intraclass correlation coefficient ICC(2,1)=0.47 (95% CI 0.06-0.75) indicated poor reliability. The mean absolute percentage error between the predicted and the actual VO2max was 15.79%, while the root mean square error was 8.85 mL/kg/minute. The analysis further revealed higher accuracy when focusing on participants with good fitness levels (mean absolute percentage error=14.59%; root-mean-square error=7.22 ml/kg/minute; ICC(2,1)=0.60 95% CI 0.09-0.87). CONCLUSIONS: Similar to other smartwatches, the Apple Watch also overestimates or underestimates the VO2max in individuals with poor or excellent fitness levels, respectively. Assessing the accuracy and reliability of the Apple Watch's VO2max estimation is crucial for determining its suitability as an alternative to laboratory testing. The findings of this study will apprise researchers, physical training professionals, and end users of wearable technology, thereby enhancing the knowledge base and practical application of such devices in assessing cardiorespiratory fitness parameters.

The research landscape of bipolar disorder in Germany: productive, but underfunded.

BACKGROUND: The recurrent mental illness bipolar disorder is a major burden on the healthcare system, which underlines the importance of research into this disease. Germany is one of the most productive countries in this research activity. This bibliometric analysis aims to outline the social and conceptual structure of the German research landscape on bipolar disorder over the last decade. Furthermore, we provide a short overview over current public funding. RESULTS: Concerning the social structure, most of the German publications were collaboration projects, both with a national but also international orientation, in the latter case predominantly with countries of the global North. Analysis of the conceptual structure of German research activity identified psychiatric genetics, early recognition of bipolar disorder, neuroimaging, and pharmacological interventions as important topics within the field. In the context of a survey, only few publicly funded research projects were reported, many of which did not exclusively investigate bipolar disorder but followed a transdiagnostic approach. CONCLUSIONS: Our bibliometric analysis revealed internationally well-networked German research activities on bipolar disorder. In stark contrast to its high prevalence and correspondingly high financial burden to the healthcare system, current grant support for research on this illness is strikingly low, particularly concerning the development of novel treatments.

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.

Somatic burden of attention-deficit/hyperactivity disorder across the lifecourse.

OBJECTIVE: A thorough and comprehensive knowledge base on the extent of comorbidity of attention-deficit/hyperactivity disorder (ADHD) and somatic conditions is needed. METHOD: We compared the prevalence of a wide range of somatic conditions in individuals with and without ADHD and described sex and lifecourse differences. Individuals with an ADHD diagnosis (N = 87,394) and age and sex-matched individuals without an ADHD diagnosis were identified from a large health claims dataset representative of the general German population, including both primary and specialized care (N = 4.874,754). Results were provided for the full sample as well as stratified for sex and age (<12 years, 13-17 years, 18-29 years, 30-59 years, ≥60 years). RESULTS: The results showed that ADHD is associated with a wide variety of somatic conditions across the entire lifecourse. Specifically neurological disorders such as Parkison's disease (odds ratio [OR]: 5.21) and dementia (OR: 2.23), sleep-related disorders (OR: 2.38) and autoimmune disorders affecting the musculoskeletal, digestive, and endocrine system (fibromyalgia OR: 3.33; lupus OR: 2.17) are strongly and significantly associated with ADHD. Additionally, ADHD is associated with higher occurrence of common acute diseases typically treated by the general practitioner, hinting at an overall general lower health status. Sex differences in somatic comorbidity were not prominent. Age differences, in contrast, stood out: in particular endocrine, cardiovascular, and neurological disorders had an early onset in individuals with compared to individuals without ADHD. CONCLUSION: This research underlines the high burden of disease due to somatic conditions among individuals with ADHD. The findings indicate the need for preventive measures to reduce comorbidity.

Medical comorbidities in bipolar disorder (BIPCOM): clinical validation of risk factors and biomarkers to improve prevention and treatment. Study protocol.

BACKGROUND: BIPCOM aims to (1) identify medical comorbidities in people with bipolar disorder (BD); (2) examine risk factors and clinical profiles of Medical Comorbidities (MC) in this clinical group, with a special focus on Metabolic Syndrome (MetS); (3) develop a Clinical Support Tool (CST) for the personalized management of BD and medical comorbidities. METHODS: The BIPCOM project aims to investigate MC, specifically MetS, in individuals with BD using various approaches. Initially, prevalence rates, characteristics, genetic and non-genetic risk factors, and the natural progression of MetS among individuals with BD will be assessed by analysing Nordic registers, biobanks, and existing patient datasets from 11 European recruiting centres across 5 countries. Subsequently, a clinical study involving 400 participants from these sites will be conducted to examine the clinical profiles and incidence of specific MetS risk factors over 1 year. Baseline assessments, 1-year follow-ups, biomarker analyses, and physical activity measurements with wearable biosensors, and focus groups will be performed. Using this comprehensive data, a CST will be developed to enhance the prevention, early detection, and personalized treatment of MC in BD, by incorporating clinical, biological, sex and genetic information. This protocol will highlight the study's methodology. DISCUSSION: BIPCOM's data collection will pave the way for tailored treatment and prevention approaches for individuals with BD. This approach has the potential to generate significant healthcare savings by preventing complications, hospitalizations, and emergency visits related to comorbidities and cardiovascular risks in BD. BIPCOM's data collection will enhance BD patient care through personalized strategies, resulting in improved quality of life and reduced costly interventions. The findings of the study will contribute to a better understanding of the relationship between medical comorbidities and BD, enabling accurate prediction and effective management of MetS and cardiovascular diseases. TRIAL REGISTRATION: ISRCTN68010602 at https://www.isrctn.com/ISRCTN68010602 . Registration date: 18/04/2023.

Larger putamen in individuals at risk and with manifest bipolar disorder.

BACKGROUND: Individuals at risk for bipolar disorder (BD) have a wide range of genetic and non-genetic risk factors, like a positive family history of BD or (sub)threshold affective symptoms. Yet, it is unclear whether these individuals at risk and those diagnosed with BD share similar gray matter brain alterations. METHODS: In 410 male and female participants aged 17-35 years, we compared gray matter volume (3T MRI) between individuals at risk for BD (as assessed using the EPIbipolar scale; n = 208), patients with a DSM-IV-TR diagnosis of BD (n = 87), and healthy controls (n = 115) using voxel-based morphometry in SPM12/CAT12. We applied conjunction analyses to identify similarities in gray matter volume alterations in individuals at risk and BD patients, relative to healthy controls. We also performed exploratory whole-brain analyses to identify differences in gray matter volume among groups. ComBat was used to harmonize imaging data from seven sites. RESULTS: Both individuals at risk and BD patients showed larger volumes in the right putamen than healthy controls. Furthermore, individuals at risk had smaller volumes in the right inferior occipital gyrus, and BD patients had larger volumes in the left precuneus, compared to healthy controls. These findings were independent of course of illness (number of lifetime manic and depressive episodes, number of hospitalizations), comorbid diagnoses (major depressive disorder, attention-deficit hyperactivity disorder, anxiety disorder, eating disorder), familial risk, current disease severity (global functioning, remission status), and current medication intake. CONCLUSIONS: Our findings indicate that alterations in the right putamen might constitute a vulnerability marker for BD.

When a test is more than just a test: Findings from patient interviews and survey in the trial of a technology to measure antidepressant medication response (the PReDicT Trial).

BACKGROUND: A RCT of a novel intervention to detect antidepressant medication response (the PReDicT Test) took place in five European countries, accompanied by a nested study of its acceptability and implementation presented here. The RCT results indicated no effect of the intervention on depression at 8 weeks (primary outcome), although effects on anxiety at 8 weeks and functioning at 24 weeks were found. METHODS: The nested study used mixed methods. The aim was to explore patient experiences of the Test including acceptability and implementation, to inform its use within care. A bespoke survey was completed by trial participants in five countries (n = 778) at week 8. Semi-structured interviews were carried out in two countries soon after week 8 (UK n = 22, Germany n = 20). Quantitative data was analysed descriptively; for qualitative data, thematic analysis was carried out using a framework approach. Results of the two datasets were interrogated together. OUTCOMES: Survey results showed the intervention was well received, with a majority of participants indicating they would use it again, and it gave them helpful extra information; a small minority indicated the Test made them feel worse. Qualitative data showed the Test had unexpected properties, including: instigating a process of reflection, giving participants feedback on progress and new understanding about their illness, and making participants feel supported and more engaged in treatment. INTERPRETATION: The qualitative and quantitative results are generally consistent. The Test's unexpected properties may explain why the RCT showed little effect, as properties were experienced across both trial arms. Beyond the RCT, the qualitative data sheds light on measurement reactivity, i.e., how measurements of depression can impact patients.

Exploring the incidence of inadequate response to antidepressants in the primary care of depression.

Data from the UK suggests 13-55 % of depression patients experience some level of treatment resistance. However, little is known about how physicians manage inadequate response to antidepressants in primary care. This study aimed to explore the incidence of inadequate response to antidepressants in UK primary care. One-hundred-eighty-four medication-free patients with low mood initiated antidepressant treatment and monitored severity of depression symptoms, using the QIDS-SR16, for 48 weeks. Medication changes, visits to healthcare providers, and health-related quality of life were also recorded. Patients were classified into one of four response types based on their QIDS scores at three study timepoints: persistent inadequate responders (<50 % reduction in baseline QIDS at all timepoints), successful responders (≥50 % reduction in baseline QIDS at all timepoints), slow responders (≥50 % reduction in QIDS at week 48, despite earlier inadequate responses), and relapse (initial ≥50 % reduction in baseline QIDS, but inadequate response by week 48). Forty-eight weeks after initiating treatment 47 % of patients continued to experience symptoms of depression (QIDS >5), and 20 % of patients had a persistent inadequate response. Regardless of treatment response, 96 % (n = 176) of patients did not visit their primary care physician over the 40-week follow-up period. These results suggest that despite receiving treatment, a considerable proportion of patients with low mood remain unwell and fail to recover. Monitoring depression symptoms remotely can enable physicians to identify inadequate responders, allowing patients to be reassessed or referred to secondary services, likely improving patients' quality of life and reducing the socioeconomic impacts of chronic mental illness.

Validation of the predictive value of BDNF -87 methylation for antidepressant treatment success in severely depressed patients-a randomized rater-blinded trial.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is essential for antidepressant treatment of major depressive disorder (MDD). Our repeated studies suggest that DNA methylation of a specific CpG site in the promoter region of exon IV of the BDNF gene (CpG -87) might be predictive of the efficacy of monoaminergic antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and others. This trial aims to evaluate whether knowing the biomarker is non-inferior to treatment-as-usual (TAU) regarding remission rates while exhibiting significantly fewer adverse events (AE). METHODS: The BDNF trial is a prospective, randomized, rater-blinded diagnostic study conducted at five university hospitals in Germany. The study's main hypothesis is that {1} knowing the methylation status of CpG -87 is non-inferior to not knowing it with respect to the remission rate while it significantly reduces the AE rate in patients experiencing at least one AE. The baseline assessment will occur upon hospitalization and a follow-up assessment on day 49 (± 3). A telephone follow-up will be conducted on day 70 (± 3). A total of 256 patients will be recruited, and methylation will be evaluated in all participants. They will be randomly assigned to either the marker or the TAU group. In the marker group, the methylation results will be shared with both the patient and their treating physician. In the TAU group, neither the patients nor their treating physicians will receive the marker status. The primary endpoints include the rate of patients achieving remission on day 49 (± 3), defined as a score of ≤ 10 on the Hamilton Depression Rating Scale (HDRS-24), and the occurrence of AE. ETHICS AND DISSEMINATION: The trial protocol has received approval from the Institutional Review Boards at the five participating universities. This trial holds significance in generating valuable data on a predictive biomarker for antidepressant treatment in patients with MDD. The findings will be shared with study participants, disseminated through professional society meetings, and published in peer-reviewed journals. TRIAL REGISTRATION: German Clinical Trial Register DRKS00032503. Registered on 17 August 2023.

Bright light therapy versus physical exercise to prevent co-occurring depression in adolescents and young adults with attention-deficit/hyperactivity disorder: a multicentre, three-arm, randomised controlled, pilot phase-IIa trial.

Depression is common in attention-deficit/hyperactivity disorder (ADHD), but preventive behavioural interventions are lacking. This randomised controlled, pilot phase-IIa trial aimed to study a physical exercise intervention (EI) and bright light therapy (BLT)-both implemented and monitored in an individual, naturalistic setting via a mobile health (m-health) system-for feasibility of trial design and interventions, and to estimate their effects on depressive symptoms in young people with ADHD. Two hundred seven participants aged 14-45 years were randomised to 10-week add-on intervention of either BLT (10,000 lx; daily 30-min sessions) (n = 70), EI (aerobic and muscle-strengthening activities 3 days/ week) (n = 69), or treatment-as-usual (TAU) (n = 68), of whom 165 (80%) were retained (BLT: n = 54; EI: n = 52; TAU: n = 59). Intervention adherence (i.e. ≥ 80% completed sessions) was very low for both BLT (n = 13, 22%) and EI (n = 4, 7%). Usability of the m-health system to conduct interventions was limited as indicated by objective and subjective data. Safety was high and comparable between groups. Changes in depressive symptoms (assessed via observer-blind ratings, Inventory of Depressive Symptomatology) between baseline and end of intervention were small (BLT: -0.124 [95% CI: -2.219, 1.971], EI: -2.646 [95% CI: -4.777, -0.515], TAU: -1.428 [95% CI: -3.381, 0.526]) with no group differences [F(2,153) = 1.45, p = 0.2384]. These findings suggest that the m-health approach did not achieve feasibility of EI and BLT in young people with ADHD. Prior to designing efficacy studies, strategies how to achieve high intervention adherence should be specifically investigated in this patient group. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03371810, 13 December 2017.

A systematic review of progranulin concentrations in biofluids in over 7,000 people-assessing the pathogenicity of GRN mutations and other influencing factors.

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.

Mental health improvement after the COVID-19 pandemic in individuals with psychological distress.

The COVID-19 pandemic and associated countermeasures had an immensely disruptive impact on people's lives. Due to the lack of systematic pre-pandemic data, however, it is still unclear how individuals' psychological health has been affected across this incisive event. In this study, we analyze longitudinal data from two healthy samples (N = 307) to provide quasi-longitudinal insight into the full trajectory of psychological burden before (baseline), during the first peak, and at a relative downturn of the COVID-19 pandemic. Our data indicated a medium rise in psychological strain from baseline to the first peak of the pandemic (d = 0.40). Surprisingly, this was overcompensated by a large decrease of perceived burden until downturn (d = - 0.93), resulting in a positive overall effect of the COVID-19 pandemic on mental health (d = 0.44). Accounting for this paradoxical positive effect, our results reveal that the post-pandemic increase in mental health is driven by individuals that were already facing psychological challenges before the pandemic. These findings suggest that coping with acute challenges such as the COVID-19 pandemic can stabilize previously impaired mental health through reframing processes.

External cues improve visual working memory encoding in the presence of salient distractors in schizophrenia.

BACKGROUND: People with schizophrenia (PSZ) are impaired in attentional prioritization of non-salient but relevant stimuli over salient distractors during visual working memory (VWM) encoding. Conversely, guidance of top-down attention by external predictive cues is intact. Yet, it is unknown whether this preserved ability can help PSZ encode more information in the presence of salient distractors. METHODS: We employed a visuospatial change-detection task using four Gabor patches with differing orientations in 66 PSZ and 74 healthy controls (HCS). Two Gabor patches flickered which were designated either as targets or distractors and either a predictive or a non-predictive cue was displayed to manipulate top-down attention, resulting in four conditions. RESULTS: We observed significant effects of group, salience and cue as well as significant interactions of salience by cue, group by salience and group by cue. Across all conditions, PSZ stored significantly less information in VWM than HCS. PSZ stored significantly less non-flickering than flickering information with a non-predictive cue. However, PSZ stored significantly more flickering and non-flickering information with a predictive cue. CONCLUSIONS: Our findings indicate that control of attentional selection is impaired in schizophrenia. We demonstrate that additional top-down information significantly improves performance in PSZ. The observed deficit in attentional control suggests a disturbance of GABAergic inhibition in early visual areas. Moreover, our findings are indicative of a mechanism for enhancing attentional control in PSZ, which could be utilized by pro-cognitive interventions. Thus, the current paradigm is suitable to reveal both preserved and compromised cognitive component processes in schizophrenia.

Identifying genetic differences between bipolar disorder and major depression through multiple GWAS.

Background: Accurate diagnosis of bipolar disorder (BD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A key reason is that the first manic episode is often preceded by a depressive one, making it difficult to distinguish BD from unipolar major depressive disorder (MDD). Aims: Here, we use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores that may aid early differential diagnosis. Methods: Based on individual genotypes from case-control cohorts of BD and MDD shared through the Psychiatric Genomics Consortium, we compile case-case-control cohorts, applying a careful merging and quality control procedure. In a resulting cohort of 51,149 individuals (15,532 BD cases, 12,920 MDD cases and 22,697 controls), we perform a variety of GWAS and polygenic risk scores (PRS) analyses. Results: While our GWAS is not well-powered to identify genome-wide significant loci, we find significant SNP-heritability and demonstrate the ability of the resulting PRS to distinguish BD from MDD, including BD cases with depressive onset. We replicate our PRS findings, but not signals of individual loci in an independent Danish cohort (iPSYCH 2015 case-cohort study, N=25,966). We observe strong genetic correlation between our case-case GWAS and that of case-control BD. Conclusions: We find that MDD and BD, including BD with a depressive onset, are genetically distinct. Further, our findings support the hypothesis that Controls - MDD - BD primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BD and, importantly, BD with depressive onset from MDD.

The influence of the COMT Val158Met polymorphism on prefrontal TDCS effects on aggression.

Increasing dorsolateral prefrontal cortex (DLPFC) activity by anodal transcranial direct current stimulation (tDCS) enhances cognitive control and might reduce aggression. The Val158Met polymorphism within the catechol-O-methyltransferase gene (rs4680) plays a pivotal role in prefrontal dopamine signaling, displaying associations with aggressive behavior, and potentially influencing the effects of tDCS. In a double-blind, sham-controlled study, we investigated the influence of rs4680 on tDCS effects on aggression. While undergoing functional magnetic resonance imaging, 89 healthy male participants performed the Taylor aggression paradigm before and immediately after tDCS. Actively stimulated participants (n = 45) received anodal tDCS (1.5 mA) for 20 min targeting the right DLPFC. Carriers of the val-allele (val+; n = 46; active tDCS n = 23) were compared to met-allele homozygotes (val-; n = 43; active tDCS n = 22). Analysis revealed decreased aggressive behavior in the val- group following active tDCS (p < 0.001). The val+ group showed increased aggression during the second session (p < 0.001) with an even higher increase following active as compared to sham tDCS (p < 0.001). No effects of stimulation or rs4680 on brain activation were found. Our study provides evidence for opposite tDCS effects on aggressive behavior in val-carriers and val-noncarriers. By shedding light on genetic factors predicting tDCS responsivity, the study will help to pave the way toward individualized-and thus more effective-tDCS treatment options.