Bipolar At-Risk Criteria and Risk of Bipolar Disorder Over 10 or More Years.

Importance: Predicting the onset of bipolar disorder (BD) could facilitate preventive treatments. Among risk measures, bipolar at-risk (BAR) criteria have shown promise in predicting onset of bipolar disorder in the first year in clinical cohorts; however, it is not known whether BAR criteria are associated with the onset of BD in the longer term. Objective: To assess the association of BAR criteria with onset of BD over 10 to 13 years follow-up. Design, Setting, and Participants: This prospective cohort study, completed between May 1, 2020, and November 7, 2022, included consenting people seeking help for nonpsychotic major mental health difficulties, including mood, personality, and substance use disorders, who were originally recruited at ages 15 to 25 years from a tertiary youth mental health setting in metropolitan Melbourne, Victoria, Australia, from May 1, 2008, to September 30, 2010. Exposure: Meeting BAR criteria at baseline. Criteria included subthreshold mania, cyclothymic features, subthreshold depression, and family history of BD. A matched clinical comparison group was recruited from the same help-seeking population. Main Outcomes and Measures: The primary outcome was expert consensus diagnosis of BD I or II based on the Mini International Neuropsychiatric Interview, self-reported information collected through online assessments, and linked data on mental health service utilization in Victoria over 10 to 13 years of follow-up. Results: Among 69 eligible participants, follow-up data were available for 60 (88.2%). The mean (SD) age at the end of follow-up was 32.9 (2.8) years, and 49 (81.7%) were women. A total of 28 participants met BAR criteria, and 32 were in the comparison group. In the BAR group, 8 patients (28.6%) developed BD over a mean (SD) of 11.1 (0.7) years of follow-up, and no patients in the comparison group developed BD. The risk of developing BD was higher in the BAR group than in the non-BAR group (χ21 = 70.0; P < .001). The proportions of transitions to BD were equal in the first and second halves of the follow-up period. Conclusions and relevance: In this cohort study of participants seeking care for mental health difficulties, patients meeting the BAR criteria were significantly more likely to transition to BD over a decade after ascertainment compared with patients not meeting the BAR criteria. The findings suggest that those meeting BAR criteria may benefit from longer-term monitoring and support. Evaluation of predictive properties in longer-term studies using a risk measure will help with implementation of BAR criteria in clinical settings.

Anxiety and depression related abnormalities in socio-affective learning.

Affective distress (as observed in anxiety and depression) has been observed to be related to insufficient sensitivity to changing reinforcement during operant learning. Whether such findings are specific to anxiety or depression is unclear given a wider literature relating negative affect to abnormal learning and the possibility that relationships are not consistent across incentive types (i.e., punishment and reward) and outcomes (i.e., positive or negative). In two separate samples (n1 = 100; n2 = 88), participants completed an operant learning task with positive or negative, and neutral socio-affective feedback, designed to assess adaptive responses to changing environmental volatility. Individual parameter estimates were generated with hierarchical Bayesian modelling. Effects of manipulations were modelled by decomposing parameters into a linear combination of effects on the logit scale. While effects tended to support prior work, neither general affective distress nor anxiety or depression were consistently related to a decrease in the adaptive adjustment of learning-rates in response to changing environmental volatility (Sample 1: ßα:volatility = -0.01, 95 % HDI = -0.14, 0.13; Sample 2: ßα:volatility = -0.15, 95 % HDI = -0.37, 0.05). Interaction effects in Sample 1 suggested that while distress was associated with decrements in adaptive learning under punishment-minimisation, it was associated with improvements under reward-maximisation. While our results are broadly consistent with prior work, they suggest that the role of anxiety or depression in volatility learning, if present, is subtle and difficult to detect. Inconsistencies between our samples, along with issues of parameter identifiability complicated interpretation.

Empirically driven transdiagnostic stages in the development of mood, anxiety and psychotic symptoms in a cohort of youth followed from birth.

Staging models with transdiagnostic validity across mood, psychotic, and anxiety disorders could advance early intervention efforts as well as our understanding of the common underpinnings of such psychopathology. However, there are few well-supported operationalisations for such transdiagnostic models, particularly in community-based samples. We aimed to explore the inter-relationships among mood, psychotic, and anxiety symptom stages, and their common risk factors to develop data-informed transdiagnostic stages. We included participants from the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective ongoing birth cohort study. We developed operational thresholds for stages of depressive, hypomanic, anxiety, and psychotic symptoms based on the existing literature, refined further by expert consensus. We selected 1b level as the primary stage or outcome of interest. This represents moderate symptoms that are likely to be associated with the onset of the need for clinical mental health care. We used questionnaire and clinic data completed by young people ages 18 and 21 years. We used descriptive methods and network analyses to examine the overlap among Stage 1b psychopathology. We then examined the patterns of relationships between several risk factors and 1b stages using logistic regressions. Among 3269 young people with data available to determine all symptom stages, 64.3% were female and 96% Caucasian. Descriptive and network analyses indicated that 1b level depressive, anxiety, and psychotic symptom stages were inter-related while hypomania was not. Similarly, anxiety, depressive, and psychotic 1b stages were associated with the female sex, more emotional and behavioral difficulties in early adolescence, and life events in late adolescence. Hypomania was not related to any of these risk factors. Given their inter-relationships and similar risk factors, anxiety, psychotic and depressive, symptoms could be combined to form a transdiagnostic stage in this cohort. Such empirical transdiagnostic stages could help with prognostication and indicated prevention in youth mental health.

Characterizing the time course of decision-making in change detection.

We propose a novel modeling framework for characterizing the time course of change detection based on information held in visual short-term memory (VSTM). Specifically, we seek to answer whether change detection is better captured by a first-order integration model, in which information is pooled from each location, or a second-order integration model, in which each location is processed independently. We diagnose whether change detection across locations proceeds in serial or parallel and how processing is affected by the stopping rule (i.e., detecting any change vs. detecting all changes; Experiment 1) and how the efficiency of detection is affected by the number of changes in the display (Experiment 2). We find that although capacity is generally limited in both tasks, the architecture varies from parallel self-terminating in the OR task to serial self-terminating in the AND task. Our novel framework allows model comparisons across a large set of models ruling out several competing explanations of change detection. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

X-linked creatine transporter deficiency results in prolonged QTc and increased sudden death risk in humans and disease model.

PURPOSE: Creatine transporter deficiency (CTD) is a rare X-linked disorder of creatine transport caused by pathogenic variants in SLC6A8 (Xq28). CTD features include developmental delay, seizures, and autism spectrum disorder. This study was designed to investigate CTD cardiac phenotype and sudden death risk. METHODS: We performed a cross-sectional analysis of CTD males between 2017 and 2020. Subjects underwent evaluation with electrocardiogram (ECG), echocardiography, and ambulatory ECG with comparable analysis in creatine transporter deficient mice (Slc6a8-/y) using ECG, echocardiography, exercise testing, and indirect calorimetry. RESULTS: Eighteen subjects with CTD (18 males, age 7.4 [3.8] years) were evaluated: seven subjects (39%) had QTc ≥ 470 milliseconds: 510.3 ± 29.0 vs. 448.3 ± 15.9, P < 0.0001. The QTc ≥ 470 milliseconds cohort had increased left ventricular internal dimension (diastole) ([LVIDd] Z-score: 0.22 ± 0.74, n = 7 vs. -0.93 ± 1.0, n = 11, P = 0.0059), and diminished left ventricular posterior wall dimension (diastole) ([LVPWDd, in mm]: 5.0 ± 0.6, n = 7 vs. 5.7 ± 0.8, n = 11, P = 0.0183), when compared to subjects with normal or borderline QTc prolongation. Similar ECG and echocardiographic abnormalities were seen in Slc6a8-/y mice. Additionally, Slc6a8-/y mice had diminished survival (65%). CONCLUSION: Prolonged QTc and abnormal echocardiographic parameters consistent with developing cardiomyopathy are seen in some male subjects with CTD. Slc6a8-/y mice recapitulated these cardiac abnormalities. Male CTD subjects may be at increased risk for cardiac dysfunction and sudden death.

Characterizing upper limb function in the context of activities of daily living in CLN3 disease.

In CLN3 disease, impairments in motor function are frequently reported to have later onset compared to visual and cognitive decline, but upper limb motor function has yet to be explored in this population. In a cohort of 22 individuals with CLN3, we used a novel application of multiple measures to (1) characterize motor function, particularly of the upper limbs, in activities of daily living (ADLs), and (2) explore associations between motor function and age as well as visual ability, disease severity, and cognitive function, as evaluated by the Unified Batten Disease Rating Scale (UBDRS), a validated CLN3 disease measure. ADLs that required coordination, speed, and fine motor control were particularly challenging for children with CLN3 based on item-level performance across direct assessments (Jebsen-Taylor Hand Function Test [JTHFT] and MyoSet Tools) and caregiver reports (Pediatric Evaluation of Disability Inventory-Computer Adaptive Testing [PEDI-CAT] and Patient-Reported Outcomes Measurement Information System [PROMIS] Pediatric Upper Extremity). Poorer visual ability, disease severity, and cognitive function were associated with worse performance on these measures, whereas age had limited impact. These findings support the need for children with CLN3 to receive skilled clinical evaluation and treatment tailored to their individual needs, particularly in the context of ADLs, as their symptom profile progresses.

Evaluation of age of death in Niemann-Pick disease, type C: Utility of disease support group websites to understand natural history.

Niemann-Pick disease, type C (NPC) is a neurodegenerative lysosomal storage disease affecting the visceral organs and the central nervous system. The age of initial presentation varies from fetal to adult onset, although childhood onset is most common. The life expectancy for the full spectrum of NPC patients is not well defined, and it is unknown if current supportive care impacts the natural history. In order to assess age of death for a large cohort of NPC patients, we "crowd-sourced" age and year of death from information posted on disease support group website memorial walls. We analyzed data from 338 individuals who died between 1968 and 2018. In addition to age of death, gender can be inferred from given names and photographs. The median age of death was 13 years with a range from 0.1-69 years. Although sex significantly affects survival of NPC1 mutant mice, we did not observe a gender dependent survival difference in NPC patients. Median age of survival across time increased between the earliest patients and the most recently deceased patient; however, we found no significant change in survival over the last 20 years. These data suggest that supportive medical care has not impacted survival in the recent past and provides support for the use of historic controls in evaluating therapeutic interventions.