Attitudes toward risk and ambiguity significantly influence how individuals assess and value rewards. This fMRI study examines the reward valuation process under conditions of uncertainty and investigates the associated neural mechanisms in individuals who engage in nonsuicidal self-injury (NSSI) as a coping mechanism for psychological pain.

The study involved 44 unmedicated individuals who reported five or more NSSI episodes in the past year, along with 42 age-, sex-, handedness-, IQ-, and socioeconomic status-matched controls. During the fMRI scans, all participants were presented with decision-making scenarios involving uncertainty, both in terms of risk (known probabilities) and ambiguity (unknown probabilities).

In the NSSI group, aversive attitudes toward ambiguity were correlated with increased emotion reactivity and greater method versatility. Whole-brain analysis revealed notable group-by-condition interactions in the right middle cingulate cortex and left hippocampus. Specifically, the NSSI group showed decreased neural activation under ambiguity v. risk compared to the control group. Moreover, reduced hippocampal activation under ambiguity in the NSSI group was associated with increased emotion regulation problems.

This study presents the first evidence of reduced brain activity in specific regions during value-based decision-making under conditions of ambiguity in individuals with NSSI. These findings have important clinical implications, particularly concerning emotion dysregulation in this population. This study indicates the need for interventions that support and guide individuals with NSSI to promote adaptive decision-making in the face of ambiguous uncertainty.

Major theories link threat learning processes to anxiety symptoms, which typically emerge during adolescence. While this developmental stage is marked by substantial maturation of the neural circuity involved in threat learning, research directly examining adolescence-specific patterns of neural responding during threat learning is scarce. This study compared adolescents and adults in acquisition and extinction of conditioned threat responses assessed at the cognitive, psychophysiological, and neural levels, focusing on the late positive potential (LPP), an event-related potential (ERP) component indexing emotional valence.

Sixty-five adults and 63 adolescents completed threat acquisition and extinction, 24 h apart, using the bell conditioning paradigm. Self-reported fear, skin conductance responses (SCR), and ERPs were measured.

Developmental differences emerged in neural and psychophysiological responses during threat acquisition, with adolescents displaying heightened LPP responses to threat and safety cues as well as heightened threat-specific SCR compared to adults. During extinction, SCR suggested comparable reduction in conditioned threat responses across groups, while LPP revealed incomplete extinction only among adolescents. Finally, age moderated the link between anxiety severity and LPP-assessed extinction, whereby greater anxiety severity was associated with reduced extinction among younger participants.

In line with developmental theories, adolescence is characterized by a specific age-related difficulty adapting to diminishing emotional significance of prior threats, contributing to heightened vulnerability to anxiety symptoms. Further, LPP appears to be sensitive to developmental differences in threat learning and may thus potentially serve as a useful biomarker in research on adolescents, threat learning, and anxiety.

Effort-based decision-making has been proposed as a potential mechanism contributing to transdiagnostic motivational deficits in psychotic disorder and bipolar disorder. However, very limited information is available about deficits in effort-cost-decision-making in the early stages of psychotic disorder and no study has investigated effort allocation deficits before the onset of bipolar disorder. Our aim was to investigate effort-based-decision-making in ultra-high-risk for psychosis (UHR-P) and bipolar disorder (UHR-BD).

Effort-cost decision-making performance was evaluated in UHR-P (n = 72) and UHR-BD (n = 68) and healthy controls (n = 38). Effort-Expenditure for Reward Task (EEfRT) was used.

Compared to controls, both UHR-P and UHR-BD groups were associated with a reduced possibility to choose the harder task when the reward magnitudes and/or the likelihood of receiving the reward were high. In both groups, effort allocation abnormalities were associated with poor social functioning.

The current findings suggest that difficulties in effort-cost computation are transdiagnostic markers of illness liability in psychotic and bipolar disorders. In early intervention services, effort-based decision-making abnormalities should be considered as a target for interventions to manage motivational deficits in individuals at high risk for psychosis and BD.

Although numerous studies have examined the effects of psychological treatments for obsessive-compulsive disorder (OCD), their overall effectiveness remains unclear. We aimed to estimate their overall effect by combining all available randomized controlled trials (RCTs) comparing psychological treatments to control groups for OCD.

We conducted a meta-analysis of 48 RCTs with 55 comparisons published between 1992 and 1 January 2023. The primary outcome was OCD symptom severity, with Hedges' g calculated at post-treatment and follow-up. Random-effects models were employed for all analyses, and the risk of bias was assessed.

In general, psychological treatments demonstrated a significantly large effect (g = −1.14; 95% CI [−1.31 to −0.97]; I2 = 72.23%) on reducing OCD symptom severity post-treatment, this finding remained consistent across measures and after excluding outliers, but lost significance in the sensitivity analysis for only studies with low risk of bias. Type of treatment, control group and treatment format were associated with treatment effects. Moreover, more severe baseline OCD symptom severity predicted higher degree of treatment efficacy. No significant differences were observed in dropout rates between the treatment and control groups. Treatment effects lost significance at 3–6 and 6–12 month follow-ups. 87% of RCTs were rated at high risk of bias.

Psychological treatments are effective in reducing OCD symptom severity. However, caution should be exercised when interpreting these results due to the high heterogeneity and risk of bias across RCTs. Future studies with more rigorous methodology are required, as well as studies examining their long-term effectiveness.

Adolescents often experience a heightened incidence of depressive symptoms, which can persist without early intervention. However, adolescents often struggle to identify depressive symptoms, and even when they are aware of these symptoms, seeking help is not always their immediate response. This study aimed to explore the relationship between passively collected digital data, specifically keystroke and stylus data collected via mobile devices, and the manifestation of depressive symptoms.

A total of 927 first-year middle school students from schools in Seoul solved Korean language and math problems. Throughout this study, 77 types of keystroke and stylus data were collected, including parameters such as the number of key presses, tap pressure, stroke speed, and stroke acceleration. Depressive symptoms were measured using the self-rated Patient Health Questionnaire-9 (PHQ-9).

Multiple regression analysis highlighted the significance of stroke length, speed, and acceleration, the average y-coordinate, the tap pressure, and the number of incorrect answers in relation to PHQ-9 scores. The keystroke and stylus metadata were able to reflect mood, energy, cognitive abilities, and psychomotor symptoms among adolescents with depressive symptoms.

This study demonstrates the potential of automatically collected data during school exams or classes for the early screening of clinical depressive symptoms in students. This study has the potential to serve as a cornerstone in the development of digital data frameworks for the early detection of depressive symptoms in adolescents.

Different aspects of social relationships (e.g., social network size or loneliness) have been associated with dementia risk, while their overlap and potentially underlying pathways remain largely unexplored. This study therefore aimed to (1) discriminate between different facets of social relationships by means of factor analysis, (2) examine their associations with dementia risk, and (3) assess mediation by depressive symptoms.

Thirty-six items from questionnaires on social relationships administered in Wave 2 (2004/2005) of the English Longitudinal Study of Ageing (n = 7536) were used for exploratory and confirmatory factor analysis. Factors were then used as predictors in Cox proportional hazard models with dementia until Wave 9 as outcome, adjusted for demographics and cardiovascular risk factors. Structural equation modeling tested mediation by depressive symptoms through effect decomposition.

Factor analyses identified six social factors. Across a median follow-up time of 11.8 years (IQR = 5.9–13.9 years), 501 people developed dementia. Higher factor scores for frequency and quality of contact with children (HR = 0.88; p = 0.021) and more frequent social activity engagement (HR = 0.84; p < 0.001) were associated with lower dementia risk. Likewise, higher factor scores for loneliness (HR = 1.13; p = 0.011) and negative experiences of social support (HR = 1.10; p = 0.047) were associated with higher dementia risk. Mediation analyses showed a significant partial effect mediation by depressive symptoms for all four factors. Additional analyses provided little evidence for reverse causation.

Frequency and quality of social contacts, social activity engagement, and feelings of loneliness are associated with dementia risk and might be suitable targets for dementia prevention programs, partly by lowering depressive symptoms.

Shame is experienced as a threat to social self, and so activates threat-protective responses. There is evidence that shame has trauma-like characteristics, suggesting it can be understood within the same conceptual framework as trauma and dissociation. Evidence for causal links among trauma, dissociation, and psychosis thus warrant the investigation of how shame may influence causal mechanisms for psychosis symptoms.

This study tested the interaction between dissociation and shame, specifically external shame (feeling shamed by others), in predicting psychotic-like experiences (PLEs) six months later in a general population sample (N = 314). It also tested if social safeness moderates these effects. A longitudinal, online questionnaire design tested a moderation model (dissociation-shame) and a moderated moderation model (adding social safeness), using multiple regressions with bootstrap procedures.

Although there was no direct effect of dissociation on PLEs six months later, there was a significant interaction effect with shame, controlling for PLEs at baseline. There were complex patterns in the directions of effects: For high-shame-scorers, higher dissociation predicted higher PLE scores, but for low-shame-scorers, higher dissociation predicted lower PLE scores. Social safeness was found to significantly moderate these interaction effects, which were unexpectedly more pronounced in the context of higher social safeness.

The results demonstrate evidence for an interaction between dissociation and shame on its impact on PLEs, which manifests particularly for those experiencing higher social safeness. This suggests a potential role of social mechanisms in both the etiology and treatment of psychosis, which warrants further testing in clinical populations.

Neurocognitive dysfunction is a transdiagnostic finding in psychopathology, but relationships among cognitive domains and general and specific psychopathology dimensions remain unclear. This study aimed to examine associations between cognition and psychopathology dimensions in a large youth cohort.

The sample (N = 9350; age 8–21 years) was drawn from the Philadelphia Neurodevelopmental Cohort. Data from structured clinical interviews were modeled using bifactor confirmatory factor analysis (CFA), resulting in an overall psychopathology (‘p’) factor score and six orthogonal psychopathology dimensions: dysphoria/distress, obsessive-compulsive, behavioral/externalizing, attention-deficit/hyperactivity, phobias, and psychosis. Neurocognitive data were aggregated using correlated-traits CFA into five factors: executive functioning, memory, complex cognition, social cognition, and sensorimotor speed. We examined relationships among specific and general psychopathology dimensions and neurocognitive factors.

The final model showed both overall and specific associations between cognitive functioning and psychopathology, with acceptable fit (CFI = 0.91; TLI = 0.90; RMSEA = 0.024; SRMR = 0.054). Overall psychopathology and most psychopathology dimensions were negatively associated with neurocognitive functioning (phobias [p < 0.0005], behavioral/externalizing [p < 0.0005], attention-deficit/hyperactivity [p < 0.0005], psychosis [p < 0.0005 to p < 0.05]), except for dysphoria/distress and obsessive-compulsive symptoms, which were positively associated with complex cognition (p < 0.05 and p < 0.01, respectively).

By modeling a broad range of cognitive and psychopathology domains in a large, diverse sample of youth, we found aspects of neurocognitive functioning shared across clinical phenotypes, as well as domain-specific patterns. Findings support transdiagnostic examination of cognitive performance to parse variability in the link between neurocognitive functioning and clinical phenotypes.

Attention deficit hyperactivity disorder (ADHD) is increasingly diagnosed in adults. People with intellectual disability have higher rates of ADHD yet there is little evidence on the presentation and pharmacological treatment of ADHD in this population or how this differs from the general population.

Retrospective cohort study using data from electronic health records. Adults with intellectual disability newly diagnosed with ADHD between 2007 and 2022 were matched to adults with ADHD without intellectual disability and their clinical features and treatments were compared.

A total of 159 adults with ADHD and intellectual disability and 648 adults with ADHD without intellectual disability formed the dataset. Adults with intellectual disability had higher rates of psychiatric co-morbidity and spent more time under mental health services than those without intellectual disability. They were more likely to have recorded agitation, aggression, hostility, and mood instability, and less likely to have poor concentration recorded in the 12 months prior to the diagnosis of ADHD. Following diagnosis, people with intellectual disability were significantly less likely to be prescribed any medication for ADHD than controls without intellectual disability (adjusted odds ratio 0.60, 95% confidence interval 0.38–0.91), and were less likely to be prescribed stimulants (27.7% v 46.0%, p < 0.001).

The presence of behaviors that challenge in adults with intellectual disability may indicate co-occurring ADHD. Further work to define the safety and efficacy of medication for ADHD in adults with intellectual disability is needed to understand differences in prescription rates and to avoid inequities in care outcomes.

Depression is a common mental health disorder that often starts during adolescence, with potentially important future consequences including ‘Not in Education, Employment or Training’ (NEET) status.

We took a structured life course modeling approach to examine how depressive symptoms during adolescence might be associated with later NEET status, using a high-quality longitudinal data resource. We considered four plausible life course models: (1) an early adolescent sensitive period model where depressive symptoms in early adolescence are more associated with later NEET status relative to exposure at other stages; (2) a mid adolescent sensitive period model where depressive symptoms during the transition from compulsory education to adult life might be more deleterious regarding NEET status; (3) a late adolescent sensitive period model, meaning that depressive symptoms around the time when most adults have completed their education and started their careers are the most strongly associated with NEET status; and (4) an accumulation of risk model which highlights the importance of chronicity of symptoms.

Our analysis sample included participants with full information on NEET status (N = 3951), and the results supported the accumulation of risk model, showing that the odds of NEET increase by 1.015 (95% CI 1.012–1.019) for an increase of 1 unit in depression at any age between 11 and 24 years.

Given the adverse implications of NEET status, our results emphasize the importance of supporting mental health during adolescence and early adulthood, as well as considering specific needs of young people with re-occurring depressed mood.

Bipolar disorder (BD) shows heterogeneous illness presentation both cross-sectionally and longitudinally. This phenotypic heterogeneity might reflect underlying genetic heterogeneity. At the same time, overlapping characteristics between BD and other psychiatric illnesses are observed at clinical and biomarker levels, which implies a shared biological mechanism between them. Incorporating these two issues in a single study design, this study investigated whether phenotypically heterogeneous subtypes of BD have a distinct polygenic basis shared with other psychiatric illnesses.

Six lifetime phenotype dimensions of BD identified in our previous study were used as target phenotypes. Associations between these phenotype dimensions and polygenic risk scores (PRSs) of major psychiatric illnesses from East Asian (EA) and other available populations were analyzed.

Each phenotype dimension showed a different association pattern with PRSs of mental illnesses. PRS for EA schizophrenia showed a significant negative association with the cyclicity dimension (p = 0.044) but a significant positive association with the psychotic/irritable mania dimension (p = 0.001). PRS of EA major depressive disorder demonstrated a significant negative association with the elation dimension (p = 0.003) but a significant positive association with the comorbidity dimension (p = 0.028).

This study demonstrates that well-defined phenotype dimensions of lifetime-basis in BD have distinct genetic risks shared with other major mental illnesses. This finding supports genetic heterogeneity in BD and suggests a pleiotropy among BD subtypes and other psychiatric disorders beyond BD. Further genomic analyses adopting deep phenotyping across mental illnesses in ancestrally diverse populations are warranted to clarify intra-diagnosis heterogeneity and inter-diagnoses commonality issues in psychiatry.

Mood disorders are characterized by great heterogeneity in clinical manifestation. Uncovering such heterogeneity using neuroimaging-based individual biomarkers, clinical behaviors, and genetic risks, might contribute to elucidating the etiology of these diseases and support precision medicine.

We recruited 174 drug-naïve and drug-free patients with major depressive disorder and bipolar disorder, as well as 404 healthy controls. T1 MRI imaging data, clinical symptoms, and neurocognitive assessments, and genetics were obtained and analyzed. We applied regional gray matter volumes (GMV) and quantile normative modeling to create maturation curves, and then calculated individual deviations to identify subtypes within the patients using hierarchical clustering. We compared the between-subtype differences in GMV deviations, clinical behaviors, cell-specific transcriptomic associations, and polygenic risk scores. We also validated the GMV deviations based subtyping analysis in a replication cohort.

Two subtypes emerged: subtype 1, characterized by increased GMV deviations in the frontal cortex, cognitive impairment, a higher genetic risk for Alzheimer's disease, and transcriptionally associated with Alzheimer's disease pathways, oligodendrocytes, and endothelial cells; and subtype 2, displaying globally decreased GMV deviations, more severe depressive symptoms, increased genetic vulnerability to major depressive disorder and transcriptionally related to microglia and inhibitory neurons. The distinct patterns of GMV deviations in the frontal, cingulate, and primary motor cortices between subtypes were shown to be replicable.

Our current results provide vital links between MRI-derived phenotypes, spatial transcriptome, genetic vulnerability, and clinical manifestation, and uncover the heterogeneity of mood disorders in biological and behavioral terms.

Psychiatric disorders and type 2 diabetes mellitus (T2DM) are heritable, polygenic, and often comorbid conditions, yet knowledge about their potential shared familial risk is lacking. We used family designs and T2DM polygenic risk score (T2DM-PRS) to investigate the genetic associations between psychiatric disorders and T2DM.

We linked 659 906 individuals born in Denmark 1990–2000 to their parents, grandparents, and aunts/uncles using population-based registers. We compared rates of T2DM in relatives of children with and without a diagnosis of any or one of 11 specific psychiatric disorders, including neuropsychiatric and neurodevelopmental disorders, using Cox regression. In a genotyped sample (iPSYCH2015) of individuals born 1981–2008 (n = 134 403), we used logistic regression to estimate associations between a T2DM-PRS and these psychiatric disorders.

Among 5 235 300 relative pairs, relatives of individuals with a psychiatric disorder had an increased risk for T2DM with stronger associations for closer relatives (parents:hazard ratio = 1.38, 95% confidence interval 1.35–1.42; grandparents: 1.14, 1.13–1.15; and aunts/uncles: 1.19, 1.16–1.22). In the genetic sample, one standard deviation increase in T2DM-PRS was associated with an increased risk for any psychiatric disorder (odds ratio = 1.11, 1.08–1.14). Both familial T2DM and T2DM-PRS were significantly associated with seven of 11 psychiatric disorders, most strongly with attention-deficit/hyperactivity disorder and conduct disorder, and inversely with anorexia nervosa.

Our findings of familial co-aggregation and higher T2DM polygenic liability associated with psychiatric disorders point toward shared familial risk. This suggests that part of the comorbidity is explained by shared familial risks. The underlying mechanisms still remain largely unknown and the contributions of genetics and environment need further investigation.

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.

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.

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.

Our findings indicate that alterations in the right putamen might constitute a vulnerability marker for BD.

Cognitive control (CC) involves a top–down mechanism to flexibly respond to complex stimuli and is impaired in schizophrenia.

This study investigated the impact of increasing complexity of CC processing in 140 subjects with psychosis and 39 healthy adults, with assessments of behavioral performance, neural regions of interest and symptom severity.

The lowest level of CC (Stroop task) was impaired in all patients; the intermediate level of CC (Faces task) with explicit emotional information was most impaired in patients with first episode psychosis. Patients showed activation of distinct neural CC and reward networks, but iterative learning based on the higher-order of CC during the trust game, was most impaired in chronic schizophrenia. Subjects with first episode psychosis, and patients with lower symptom load, demonstrate flexibility of the CC network to facilitate learning, which appeared compromised in the more chronic stages of schizophrenia.

These data suggest optimal windows for opportunities to introduce therapeutic interventions to improve CC.

Migration is a well-established risk factor for psychotic disorders, and migrant language has been proposed as a novel factor that may improve our understanding of this relationship. Our objective was to explore the association between indicators of linguistic distance and the risk of psychotic disorders among first-generation migrant groups.

Using linked health administrative data, we constructed a retrospective cohort of first-generation migrants to Ontario over a 20-year period (1992–2011). Linguistic distance of the first language was categorized using several approaches, including language family classifications, estimated acquisition time, syntax-based distance scores, and lexical-based distance scores. Incident cases of non-affective psychotic disorder were identified over a 5- to 25-year period. We used Poisson regression to estimate incidence rate ratios (IRR) for each language variable, after adjustment for knowledge of English at arrival and other factors.

Our cohort included 1 863 803 first-generation migrants. Migrants whose first language was in a different language family than English had higher rates of psychotic disorders (IRR = 1.08, 95% CI 1.01–1.16), relative to those whose first language was English. Similarly, migrants in the highest quintile of linguistic distance based on lexical similarity had an elevated risk of psychotic disorder (IRR = 1.15, 95% CI 1.06–1.24). Adjustment for knowledge of English at arrival had minimal effect on observed estimates.

We found some evidence that linguistic factors that impair comprehension may play a role in the excess risk of psychosis among migrant groups; however, the magnitude of effect is small and unlikely to fully explain the elevated rates of psychotic disorder across migrant groups.

Knowledge of sex differences in risk factors for posttraumatic stress disorder (PTSD) can contribute to the development of refined preventive interventions. Therefore, the aim of this study was to examine if women and men differ in their vulnerability to risk factors for PTSD.

As part of the longitudinal AURORA study, 2924 patients seeking emergency department (ED) treatment in the acute aftermath of trauma provided self-report assessments of pre- peri- and post-traumatic risk factors, as well as 3-month PTSD severity. We systematically examined sex-dependent effects of 16 risk factors that have previously been hypothesized to show different associations with PTSD severity in women and men.

Women reported higher PTSD severity at 3-months post-trauma. Z-score comparisons indicated that for five of the 16 examined risk factors the association with 3-month PTSD severity was stronger in men than in women. In multivariable models, interaction effects with sex were observed for pre-traumatic anxiety symptoms, and acute dissociative symptoms; both showed stronger associations with PTSD in men than in women. Subgroup analyses suggested trauma type-conditional effects.

Our findings indicate mechanisms to which men might be particularly vulnerable, demonstrating that known PTSD risk factors might behave differently in women and men. Analyses did not identify any risk factors to which women were more vulnerable than men, pointing toward further mechanisms to explain women's higher PTSD risk. Our study illustrates the need for a more systematic examination of sex differences in contributors to PTSD severity after trauma, which may inform refined preventive interventions.

Problematic drinking frequently co-occurs with depression among young adults, but often remains unaddressed in depression treatment. Evidence is insufficient on whether digital alcohol interventions can be effective in this young comorbid population. In a randomized controlled trial, we examined the effectiveness of Beating the Booze (BtB), an add-on digital alcohol intervention to complement depression treatment for young adults.

Participants were randomized to BtB + depression treatment as usual (BTB + TAU, n = 81) or TAU (n = 82). The primary outcome was treatment response, a combined measure for alcohol and depression after 6-month follow-up. Secondary outcomes were number of weekly drinks (Timeline Follow-back) and depressive symptoms (Center for Epidemiologic Studies Depression scale). Treatment response was analyzed using generalized linear modeling and secondary outcomes using robust linear mixed modeling.

Low treatment response was found due to lower than expected depression remission rates. No statistically significant between-group effect was found for treatment response after 6-month follow-up (odds ratio 2.86, p = 0.089, 95% confidence interval [CI] 0.85–9.63). For our secondary outcomes, statistically significant larger reductions in weekly drinks were found in the intervention group after 3-month (B = −4.00, p = 0.009, 95% CI −6.97 to −1.02, d = 0.27) and 6-month follow-up (B = −3.20, p = 0.032, 95% CI −6.13 to −0.27, d = 0.23). We found no statistically significant between-group differences on depressive symptoms after 3-month (B = −0.57, p = 0.732, 95% CI −3.83 to 2.69) nor after 6-month follow-up (B = −0.44, p = 0.793, 95% CI −3.69 to 2.82).

The add-on digital alcohol intervention was effective in reducing alcohol use, but not in reducing depressive symptoms and treatment response among young adults with co-occurring depressive disorders and problematic alcohol use.

Pre-registered on October 29, 2019 in the Overview of Medical Research in the Netherlands (OMON), formerly the Dutch Trial Register(https://onderzoekmetmensen.nl/en/trial/49219).