Polygenic risk scores mediating functioning outcomes through cognitive and clinical features in youth at family risk and controls.

Schizophrenia and bipolar disorder exhibit substantial clinical overlap, particularly in individuals at familial high risk, who frequently present sub-threshold symptoms before the onset of illness. Severe mental disorders are highly polygenic traits, but their impact on the stages preceding the manifestation of mental disorders remains relatively unexplored. Our study aimed to examine the influence of polygenic risk scores (PRS) on sub-clinical outcomes over a 2-year period in youth at familial high risk for schizophrenia and bipolar disorder and controls. The sample included 222 children and adolescents, comprising offspring of parents with schizophrenia (n = 38), bipolar disorder (n = 80), and community controls (n = 104). We calculated PRS for psychiatric disorders, neuroticism and cognition using the PRS-CS method. Linear mixed-effects models were employed to investigate the association between PRS and cognition, symptom severity and functioning. Mediation analyses were conducted to explore whether clinical features acted as intermediaries in the impact of PRS on functioning outcomes. SZoff exhibited elevated PRS for schizophrenia. In the entire sample, PRS for depression, neuroticism, and cognitive traits showed associations with sub-clinical features. The effect of PRS for neuroticism and general intelligence on functioning outcomes were mediated by cognition and symptoms severity, respectively. This study delves into the interplay among genetics, the emergence of sub-clinical symptoms and functioning outcomes, providing novel evidence on mechanisms underpinning the continuum from sub-threshold features to the onset of mental disorders. The findings underscore the interplay of genetics, cognition, and clinical features, providing insights for personalized early interventions.

Epigenetic age deacceleration in youth at familial risk for schizophrenia and bipolar disorder.

Epigenetic modifications occur sequentially during the lifespan, but their pace can be altered by external stimuli. The onset of schizophrenia and bipolar disorder is critically modulated by stressors that may alter the epigenetic pattern, a putative signature marker of exposure to environmental risk factors. In this study, we estimated the age-related epigenetic modifications to assess the differences between young individuals at familial high risk (FHR) and controls and their association with environmental stressors. The sample included 117 individuals (6-17 years) at FHR (45%) and a control group (55%). Blood and saliva samples were used estimate the epigenetic age with six epigenetic clocks through methylation data. Environmental risk was measured with obstetric complications, socioeconomic statuses and recent stressful life events data. Epigenetic age was correlated with chronological age. FHR individuals showed epigenetic age deacceleration of Horvath and Hannum epigenetic clocks compared to controls. No effect of the environmental risk factors on the epigenetic age acceleration could be detected. Epigenetic age acceleration adjusted by cell counts showed that the FHR group was deaccelerated also with the PedBE epigenetic clock. Epigenetic age asynchronicities were found in the young at high risk, suggesting that offspring of affected parents follow a slower pace of biological aging than the control group. It still remains unclear which environmental stressors orchestrate the changes in the methylation pattern. Further studies are needed to better characterize the molecular impact of environmental stressors before illness onset, which could be critical in the development of tools for personalized psychiatry.

Polygenic Scores and Onset of Major Mood or Psychotic Disorders Among Offspring of Affected Parents.

OBJECTIVE: Family history is an established risk factor for mental illness. The authors sought to investigate whether polygenic scores (PGSs) can complement family history to improve identification of risk for major mood and psychotic disorders. METHODS: Eight cohorts were combined to create a sample of 1,884 participants ages 2-36 years, including 1,339 offspring of parents with mood or psychotic disorders, who were prospectively assessed with diagnostic interviews over an average of 5.1 years. PGSs were constructed for depression, bipolar disorder, anxiety, attention deficit hyperactivity disorder (ADHD), schizophrenia, neuroticism, subjective well-being, p factor, and height (as a negative control). Cox regression was used to test associations between PGSs, family history of major mental illness, and onsets of major mood and psychotic disorders. RESULTS: There were 435 onsets of major mood and psychotic disorders across follow-up. PGSs for neuroticism (hazard ratio=1.23, 95% CI=1.12-1.36), schizophrenia (hazard ratio=1.15, 95% CI=1.04-1.26), depression (hazard ratio=1.11, 95% CI=1.01-1.22), ADHD (hazard ratio=1.10, 95% CI=1.00-1.21), subjective well-being (hazard ratio=0.90, 95% CI=0.82-0.99), and p factor (hazard ratio=1.14, 95% CI=1.04-1.26) were associated with onsets. After controlling for family history, neuroticism PGS remained significantly positively associated (hazard ratio=1.19, 95% CI=1.08-1.31) and subjective well-being PGS remained significantly negatively associated (hazard ratio=0.89, 95% CI=0.81-0.98) with onsets. CONCLUSIONS: Neuroticism and subjective well-being PGSs capture risk of major mood and psychotic disorders that is independent of family history, whereas PGSs for psychiatric illness provide limited predictive power when family history is known. Neuroticism and subjective well-being PGSs may complement family history in the early identification of persons at elevated risk.

Cognitive reserve and its correlates in child and adolescent offspring of patients diagnosed with schizophrenia or bipolar disorder.

AIM: To analyze cognitive reserve (CR) in child and adolescent offspring of patients diagnosed with schizophrenia (SZ-off) or bipolar disorder (BD-off) and compare them with a group of community controls (CC-off). We also aimed to investigate whether there was an association between CR and clinical and neuropsychological variables according to group. METHODS: The study included 46 SZ-off, 105 BD-off and 102 CC-off. All participants completed assessments regarding CR and clinical, neuropsychological and psychosocial functioning. CR was measured with a proxy based on premorbid intelligence, parental occupational level, educational attainment, developmental milestones and sociability. The clinical assessment included the Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime, the Semi-structured Interview for Prodromal Syndromes, and the Global Assessment Functioning scale. The neuropsychological assessment included measures of executive functioning, attention, verbal memory, working memory and processing speed. RESULTS: SZ-off showed a lower level of CR compared to BD-off and CC-off, while BD-off showed an intermediate level of CR between SZ-off and CC-off. Moreover, an association between higher CR and less lifetime psychopathology, fewer prodromal psychotic symptoms, higher psychosocial functioning, and a higher working memory score was observed in all groups, but it was stronger in SZ-off. CONCLUSIONS: CR seemed to be associated with psychopathology, clinical symptoms, psychosocial functioning, and some cognitive functions. SZ-off appeared to benefit more from a higher CR, therefore it could be considered a protective factor against the development of clinical symptomatology and cognitive impairment.

The black hole of the transition process: dropout of care before transition age in adolescents.

Recent evidence confirms the risks of discontinuity of care when young people make a transition from child and adolescent mental health services (CAMHS) to adult mental health services (AMHS), although robust data are still sparse. We aimed to identify when and how patients get lost to care during transition by tracking care pathways and identifying factors which influence dropping out of care during transition. This is a retrospective observational study of 760 patients who reached the transition age boundary within 12 months before transition time and being treated at CAMHS for at least during preceding 18 months. Data were collected at two time points: last visit to CAHMS and first visit to AHMS. Socio-demographic, clinical and service utilization variables on CAMHS treatment were collected. In the 12 months leading up to the transition boundary, 46.8% of subjects (n = 356) withdrew from CAHMS without further contact with AHMS, 9.3% withdrew from CAHMS but were referred to AHMS by other services, 29% were transferred from CAHMS to AHMS, 10% remained at CAHMS and 5% patients were transferred to alternative services. Fifty-six percent of subjects experience cessation of care before the transition age. The risk of dropout increases with shorter contact time in CAMHS, is greater in subjects without pharmacological treatment, and decreases in subjects with psychosis, bipolar disorder, eating disorders, mental retardation, and neurodevelopmental disorders. This study confirms that a large number of people drop out of care as they approach the CAMHS transition and experience discontinuity of care during this critical period.

Genetic and Structural Brain Correlates of Cognitive Subtypes Across Youth at Family Risk for Schizophrenia and Bipolar Disorder.

OBJECTIVE: Cognitive impairment is an important feature of schizophrenia (SZ) and bipolar disorder (BP) with severity across the two disorders characterized by significant heterogeneity. Youth at family risk for SZ and BP were clustered based on cognitive function and examined in terms of the clinical, genetic, and brain imaging correlates of cluster membership. METHOD: One hundred sixty participants, 32 offspring of patients with SZ, 59 offspring of patients with BP and 69 offspring of healthy control parents underwent clinical and cognitive assessments, genotyping and structural MRI. K-means clustering was used to group family risk participants based on cognitive measures. Clusters were compared in terms of cortical and subcortical brain measures as well as polygenic risk scores. RESULTS: Participants were grouped in 3 clusters with intact, intermediate, and impaired cognitive performance. The intermediate and impaired clusters had lower total brain surface area compared with the intact cluster, with prominent localization in frontal and temporal cortices. No between-cluster differences were identified in cortical thickness and subcortical brain volumes. The impaired cluster also had poorer psychosocial functioning and worse PRS-COG compared with the other 2 clusters and with offspring of healthy control parents, while there was no significant between-cluster difference in terms of PRS-SZ and PRS-BP. PRS-COG predicted psychosocial functioning, yet this effect did not appear to be mediated by an effect of PRS-COG on brain area. CONCLUSION: Stratification based on cognition may help to elucidate the biological underpinnings of cognitive heterogeneity across SZ and BP risk.

Affective symptom dimensions in early-onset psychosis over time: a principal component factor analysis of the Young Mania Rating Scale and the Hamilton Depression Rating Scale.

Early-onset psychosis (EOP) is a complex disorder characterized by a wide range of symptoms, including affective symptoms. Our aim was to (1) examine the dimensional structure of affective symptoms in EOP, (2) evaluate the predominance of the clinical dimensions and (3) assess the progression of the clinical dimensions over a 2-year period. STROBE-compliant prospective principal component factor analysis of Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale-21 (HDRS-21) at baseline, 6-months, 1-year and 2-year follow-up. We included 108 EOP individuals (mean age = 15.5 ± 1.8 years, 68.5% male). The factor analysis produced a four-factor model including the following dimensions: mania, depression/anxiety, sleep and psychosis. It explained 47.4% of the total variance at baseline, 60.6% of the total variance at 6-months follow-up, 54.5% of the total variance at 1-year follow-up and 49.5% of the total variance at 2-year follow-up. According to the variance explained, the mania factor was predominant at baseline (17.4%), 6-month follow-up (23.5%) and 2-year follow-up (26.1%), while the depression/anxiety factor was predominant at 1-year follow-up (23.1%). The mania factor was the most stable; 58.3% items that appeared in this factor (with a load > 0.4) at any time point appeared in the same factor at ≥ 3/4 time points. Affective symptoms are frequent and persistent in EOP. Mania seems to be the most predominant and stable affective dimension. However, depression and anxiety may gain predominance with time. A comprehensive evaluation of the dimensional structure and the progression of affective symptoms may offer clinical and therapeutic advantages.

Fronto-Parietal Gray Matter Volume Loss Is Associated with Decreased Working Memory Performance in Adolescents with a First Episode of Psychosis.

Cognitive maturation during adolescence is modulated by brain maturation. However, it is unknown how these processes intertwine in early onset psychosis (EOP). Studies examining longitudinal brain changes and cognitive performance in psychosis lend support for an altered development of high-order cognitive functions, which parallels progressive gray matter (GM) loss over time, particularly in fronto-parietal brain regions. We aimed to assess this relationship in a subsample of 33 adolescents with first-episode EOP and 47 matched controls over 2 years. Backwards stepwise regression analyses were conducted to determine the association and predictive value of longitudinal brain changes over cognitive performance within each group. Fronto-parietal GM volume loss was positively associated with decreased working memory in adolescents with psychosis (frontal left (B = 0.096, p = 0.008); right (B = 0.089, p = 0.015); parietal left (B = 0.119, p = 0.007), right (B = 0.125, p = 0.015)) as a function of age. A particular decrease in frontal left GM volume best predicted a significant amount (22.28%) of the variance of decreased working memory performance over time, accounting for variance in age (14.9%). No such association was found in controls. Our results suggest that during adolescence, EOP individuals seem to follow an abnormal neurodevelopmental trajectory, in which fronto-parietal GM volume reduction is associated with the differential age-related working memory dysfunction in this group.

Coronavirus infection: An immunologists' perspective.

Coronavirus infections are frequent viral infections in several species. As soon as the severe acute respiratory syndrome (SARS) appeared in the early 2000s, most of the research focused on pulmonary disease. However, disorders in immune response and organ dysfunctions have been documented. Elderly individuals with comorbidities exhibit worse outcomes in all the coronavirus that cause SARS. Disease severity in SARS-CoV-2 infection is related to severe inflammation and tissue injury, and effective immune response against the virus is still under analysis. ACE2 receptor expression and polymorphism, age, gender and immune genetics are factors that also play an essential role in patients' clinical features and immune responses and have been partially discussed. The present report aims to review the physiopathology of SARS-CoV-2 infection and propose new research topics to understand the complex mechanisms of viral infection and viral clearance.

Cognitive heterogeneity in the offspring of patients with schizophrenia or bipolar disorder: a cluster analysis across family risk.

BACKGROUND: Neurocognitive impairment is considered to lie on a continuum of severity across schizophrenia (SZ) and bipolar disorder (BP), possibly reflecting a gradient of neurodevelopmental load. Cluster analyses have identified different levels of impairment across the two disorders, from none to widespread and severe. We for the first time used this approach to examine cognitive function pooling together children and adolescents at familial risk of SZ or BP. METHODS: 220 participants, 49 offspring of individuals with schizophrenia (SZO), 90 offspring of individuals with bipolar disorder (BPO) and 81 offspring of healthy control parents (HC), aged 6 to 17 years, underwent a comprehensive clinical and cognitive assessment. Cognitive measures were used to group SZO and BPO using K-means clustering. Cognitive performance within each of the clusters was compared to that of HC and clinical variables were compared between clusters. RESULTS: We identified three cognitive subgroups: a moderate impairment group, a mild impairment group, and a cognitively intact group. Both SZO and BPO were represented in each of the clusters, yet not evenly, with a larger proportion of the SZO in the moderately impaired cluster, but also a subgroup of BPO showing moderate cognitive dysfunction. LIMITATIONS: Participants have yet to reach the age of onset for the examined disorders. CONCLUSIONS: The findings point to a range of neurodevelopmental loadings across youth at familial risk of both SZ and BP. They have therefore important implications for the stratification of cognitive functioning and the possibility to tailor interventions to individual levels of impairment.

Predictors of Bipolar Disorder Versus Schizophrenia Diagnosis in a Multicenter First Psychotic Episode Cohort: Baseline Characterization and a 12-Month Follow-Up Analysis.

OBJECTIVE: The aim of this study was to identify predisposing factors and clinical features at baseline that might help predict diagnosis of bipolar disorder vs schizophrenia in a first-episode psychosis (FEP) cohort. METHODS: In this prospective, naturalistic study, we evaluated a cohort of 335 subjects with FEP recruited from April 2009 to April 2012. Baseline features were compared between subjects with a final DSM-IV diagnosis of bipolar disorder and schizophrenia at 12-month follow-up. A binary logistic regression model was used to assess predictors of diagnosis of bipolar disorder at follow-up. RESULTS: At 12-month follow-up, 47 of the 335 subjects included in the study received the diagnosis of bipolar disorder and 105, of schizophrenia. Subjects with a final diagnosis of bipolar disorder had a higher prevalence of family history of mood disorders (38.2% vs 18.0%, P = .02), better baseline premorbid adjustment (Premorbid Adjustment Scale [PAS]: 38.4 vs 50.6, P < .01) and psychosocial functioning (Functional Assessment Short Test [FAST]: 23.6 vs 33.7, P = .001), better cognitive flexibility (number of perseverative errors on the Wisconsin Card Sorting Test [WCST]: 14.2 vs 19.7, P = .01), more manic symptoms (Young Mania Rating Scale [YMRS]: 14.1 vs 7.3, P < .01), lesser negative symptoms (Positive and Negative Syndrome Scale negative scale [PANSS-N]: 15.0 vs 22.3, P < .001), and shorter duration of untreated psychosis (144.2 vs 194.7 days, P < .01) than subjects with a schizophrenia diagnosis. Binary logistic regression model revealed that lower FAST scores (odds ratio [OR] = 0.956; P = .015), lower PANSS-N scores (OR = 0.93; P = .048), and lower number of perseverative errors on the WCST (OR = 0.946; P = .035) were significantly related to diagnosis of bipolar disorder at follow-up. CONCLUSIONS: In our FEP cohort, better psychosocial functioning, lesser negative symptoms, and better cognitive flexibility were related to diagnosis of bipolar disorder at 12-month follow-up.

Neuropsychological, clinical and environmental predictors of severe mental disorders in offspring of patients with schizophrenia.

Offspring of individuals with schizophrenia (SZCOff) are at an increased risk for this disorder. Neuropsychological decline is a core feature of the disorder and researchers have reported increasing impairments in cognition during the prodromal phase in high-risk adolescents. Additionally, factors like the presence of prodromal symptoms or specific behavioral patterns could predict, together with neurocognitive functioning, the risk of conversion to severe mental disorders in SCZOff. This study aims to compare the neuropsychological functioning of a sample of 41 SCZOff children and adolescents and 105 community control offspring (CCOff) and to develop a prediction model to examine whether neuropsychological functioning, clinical and behavioral factors predict subsequent risk of severe mental disorders. We collected demographic, clinical and neuropsychological data. We found significant differences between groups in working memory, speed of processing, verbal memory and learning, visual memory and intelligence quotient (IQ). The socioeconomic status, verbal memory, working memory and positive prodromal symptoms predicted a significant proportion of the dependent variable variance. In conclusion, SCZOff showed neurocognitive impairments in several neuropsychological domains compared to CCOff. Neuropsychological functioning, environmental factors and positive prodromal symptoms could predict the risk of onset of severe mental disorders in SCZOff.

Temperament in child and adolescent offspring of patients with schizophrenia and bipolar disorder.

Shared vulnerability in offspring of individuals with schizophrenia (SzO) and bipolar disorder (BpO) might manifest early during development through common temperament traits. Temperament dimensions in child and adolescent BpO (N = 80), SzO (N = 34) and the offspring of community controls (CcO) (N = 101) were assessed using the Revised Dimensions of Temperament Survey. The association between temperament dimensions and lifetime psychopathology (including threshold and subthreshold DSM-IV-TR diagnoses) and current socio-academic adjustment was assessed using logistic regression. Fully adjusted models showed that both BpO and SzO scored significantly lower in the positive mood dimension and in the adaptability factor than CcO, with small-medium effect sizes (Cohen's d ~ 0.3-0.5). BpO also scored lower in the activity factor and the activity dimensions than CcO (Cohen's d ~ 0.3). Lower scores in the positive mood dimension were associated with increased risk of impaired adjustment both in BpO [OR 2.30, 95% CI (1.18-4.46)] and in SzO [OR 2.87, 95% CI (1.07-7.66)]. In BpO, lower scores in positive mood were also associated with increased likelihood of internalizing [OR 1.84, 95% CI (1.28-2.64)] and externalizing disorders [OR 1.48, 95% CI (1.01-2.18)]; in SzO, higher scores in activity and flexibility were associated with increased likelihood of internalizing [OR 2.31, 95% CI (1.22-4.38)] and externalizing disorders [OR 3.28, 95% CI (1.2-9)], respectively. Early difficulties in emotion regulation might represent a shared vulnerability phenotype in BpO and SzO. The identification of extreme temperament traits could help to characterize subgroups at greater risk of psychopathology and impaired adjustment, in which targeted interventions are warranted.

Smoke, Biomass Exposure, and COPD Risk in the Primary Care Setting: The PUMA Study.

BACKGROUND: The evidence indicates that risk factors other than smoking are important in the development of COPD. It has been postulated that less traditional risk factors (eg, exposure to coal and/or biomass smoke) may interact with smoking to further increase COPD risk. This analysis evaluated the effect of exposure to biomass and smoking on COPD risk in a primary care setting in Latin America. METHODS: Subjects attending routine primary care visits, ≥40 y old, who were current or former smokers or were exposed to biomass smoke, completed a questionnaire and performed spirometry. COPD was defined as post-bronchodilator FEV1/FVC < 0.70 and the lower limit of normal. Smoking was defined by pack-years (≤ 20, 20-30, or > 30), and biomass exposure was defined as an exposure to coal or wood (for heating, cooking, or both) for ≥ 10 y. RESULTS: One thousand seven hundred forty-three individuals completed the questionnaire, and 1,540 performed spirometry. Irrespective of COPD definition, approximately 40% of COPD subjects reported exposure to biomass versus 30% of those without COPD. A higher proportion of COPD subjects (post-bronchodilator FEV1/FVC < 0.70) than those without COPD smoked > 30 pack-years (66% vs 39%); similar results were found with the lower limit of normal definition. Analysis of exposure to biomass > 10 y plus smoking > 20 pack-years (reference was no exposure) found that tobacco smoking (crude odds ratio [OR] 4.50, 95% CI 2.73-7.41; adjusted OR 3.30, 95% CI 1.93-5.63) and biomass exposure (crude OR 3.66, 95% CI 2.00-6.73; adjusted OR 2.28, 95% CI 1.18-4.41) were risk factors for COPD, with smoking a possible confounder for the association between biomass and COPD (post-bronchodilator FEV1/FVC < 0.70); similar results were found with the lower limit of normal definition. CONCLUSIONS: Subjects with COPD from primary care had a higher exposure to biomass and smoking compared with non-COPD subjects. Smoking and biomass are both risk factors for COPD, but they do not appear to have an additive effect.

Polimorfismos de número variable de repeticiones en tándem del intrón 2 de 5-htt y MUC 7 en pacientes venezolanos con asma o EPOC / 5-HTT intron 2 and MUC7 variable number of tandem repeats polymorphisms in a Venezuelan population with asthma or COPD

El asma y la enfermedad pulmonar obstructiva crónica (EPOC) son enfermedades inflamatorias crónicas. En ambas patologías existe broncoconstricción, producción de mediadores inflamatorios, hipersecreción de moco y migración de células inflamatorias. La serotonina tiene propiedades inmunomoduladoras que facilitan la broncoconstricción y su transportador (5-HTT) es el principal determinante de su concentración plasmática. Las mucinas (MUC) son glicoproteínas involucradas en la inmunidad innata local. El objetivo del presente trabajo fue estudiar la asociación entre polimorfismos de número variable de repeticiones en tándem (VNTR) del intrón 2 de 5-HTT (STin2) y MUC7 en pacientes venezolanos con asma o EPOC. El grupo de estudio consistió en 301 individuos (102 asmáticos, 99 EPOC, y 100 controles). No se observaron diferencias en las frecuencias de polimorfismos de MUC7 entre los grupos. Sin embargo, se encontró asociación entre alelos y genotipos de STin2 con presencia de asma o EPOC (p <0,001). El alelo STin2.9 tuvo un odds ratio (OR) de 0,15 (p=0,16) en los pacientes con asma, mientras que en los pacientes con EPOC los genotipos STin2.10/10 y 10/12 presentaron un OR de 0,33 (p=0,002) y 3,64 (p=0,002), respectivamente. Con relación a los haplotipos, el STin2/MUC7 10/10-6/6 se relacionó con riesgo en asma (OR=1,6, p=0,02) y protección en EPOC (OR=0,3, p=0,006) y el 10/12-6/6 (OR=3,7, p=0,002) fue un factor de riesgo para EPOC. En conclusión, en la población venezolana los polimorfismos de STin2 son importantes para definir factor de riesgo de enfermedad y, en consecuencia, el transportador de serotonina es relevante en ambas patologías.

Asthma and Chronic Obstructive Pulmonary Disease (COPD) are chronic inflammatory diseases. Both entities are characterized by bronchoconstriction, production of inflammatory mediators, mucus hypersecretion and inflammatory cell migration. Serotonin has immunomodulatory properties facilitating bronchoconstriction and its plasma concentration is transporter dependent (5-HTT). Mucins are glycoproteins involved in local innate immunity. The aim of this study was to assess the association between the variable number of tandem repeat polymorphisms (VNTR) of intron 2 of the serotonin ransporter (5-HTT) (STin2) and MUC7 in Venezuelan asthmatic or COPD patients. The group consisted of 301 individuals (102 asthmatics, 99 with COPD and 100 controls). There were no differences in the frequencies of MUC7 polymorphisms among the groups. However, there is a significant association between some alleles and genotypes with the presence of asthma or COPD (p <0.001). The STin2.9 allele had an odds ratio (OR) of 0.15 (p=0.16) in patients with asthma, while in patients with COPD, the STin2.10/10 and 10/12 genotypes had 0.33 (p=0,002) and 3.64 (p=0,002) OR, respectively. Regarding haplotypes, the STin2/ MUC7 10/10-6/6 is related to asthma risk (OR = 1.6, p=0.02) and COPD protection (OR=0.3, p=0.006) and 10/12-6/6 (OR=3.7, p=0.002), is a risk factor for COPD. In conclusion, in the Venezuelan population STin2 polymorphisms are important to define disease risk factor and consequently, the serotonin transporter is relevant to both pathologies.

A developmental approach to dimensional expression of psychopathology in child and adolescent offspring of parents with bipolar disorder.

The aim of this is to describe psychopathology, functioning and symptom dimensions accounting for subthreshold manifestations and developmental status in child and adolescent offspring of parents with bipolar disorder ("high-risk offspring"). The study population comprised 90 high-risk offspring (HR-offspring) and 107 offspring of community control parents (CC-offspring). Direct clinical observations and parental and offspring reports based on selected standardized clinical scales were used to assess offspring threshold and subthreshold diagnoses, symptoms and functioning. All outcomes were compared between the whole HR-offspring and CC-offspring samples and then by developmental status. After controlling for potential confounders, HR-offspring showed significantly poorer adjustment for childhood (r = 0.18, p = 0.014) and adolescence (r = 0.21, p = 0.048) than CC-offspring, as well as more emotional problems (r = 0.24, p = 0.001) and higher depression scores (r = 0.16, p = 0.021). As for differences in lifetime categorical diagnoses (threshold and subthreshold) between HR-offspring and CC-offspring, the prevalence of disruptive disorders was higher in pre-pubertal HR-offspring (OR 12.78 [1.45-112.42]), while prevalence of mood disorders was higher in post-pubertal HR-offspring (OR 3.39 [1.14-10.06]). Post-pubertal HR-offspring presented more prodromal (r = 0.40, p = 0.001), negative (r = 0.38, p = 0.002), manic (r = 0.22, p = 0.035) and depressive (r = 0.23, p = 0.015) symptoms than pre-pubertal HR-offspring, as well as more peer relationship problems (r = 0.31, p = 0.004), poorer childhood adjustment (r = 0.22, p = 0.044) and worse current psychosocial functioning (r = 0.27, p = 0.04). Externalizing psychopathology is more prevalent in pre-pubertal HR-offspring, while depressive and prodromal symptoms leading to functional impairment are more prominent in post-pubertal HR-offspring. Developmental approaches and dimensional measures may be useful for identifying children at high risk of developing bipolar disorder and help guide specific preventive strategies.

Clinical, Cognitive, and Neuroimaging Evidence of a Neurodevelopmental Continuum in Offspring of Probands With Schizophrenia and Bipolar Disorder.

Background: Studies in child and adolescent offspring of patients with schizophrenia or bipolar disorders may help understand the influence of neurodevelopmental factors on the premorbid phenotype of these disorders. Aims: To assess whether a combination of neurodevelopmental factors discriminates between young offspring of patients with schizophrenia (SzO) or bipolar disorder (BpO) and community controls (CcO). To assess the association between these factors and rates of psychiatric diagnoses in high risk (HR) youth. Methods: One hundred thirty-three HR offspring (47 SzO and 86 BpO) and 84 CcO, aged 6-17, underwent cross-sectional clinical, neurocognitive, and structural neuroimaging assessment. Information on perinatal events and early childhood development was also obtained. General linear mixed models were performed to assess group discrimination and association with lifetime axis I psychiatric disorders. Results: Multivariate analyses revealed that greater neurological soft signs (NSS), less total grey matter volume (GMV) and a higher frequency of obstetric complications discriminated HR offspring from CcO. When comparing each group individually, greater NSS and a higher frequency of obstetric complications discriminated SzO from CcO, and BpO from CcO, while lower intelligence also discriminated SzO from CcO and from BpO. Within HR offspring, lower intelligence and less total GMV were associated with lifetime incidence of psychiatric disorders. Conclusions: Both SzO and BpO showed evidence of neurodevelopmental insult, although this may have a greater impact in SzO. Lower intelligence and less total GMV hold potential as biomarkers of risk for psychiatric disorders in HR youth.

Cortical Morphology Characteristics of Young Offspring of Patients With Schizophrenia or Bipolar Disorder.

OBJECTIVE: Cortical surface area and thickness abnormalities have been observed in patients with schizophrenia and bipolar disorders; however, no study thus far has examined cortical morphologic measurements in children and adolescents at genetic risk for the disorders comparatively. METHOD: One hundred thirty-seven participants, including 36 offspring of patients with schizophrenia (SzO), 54 offspring of patients with bipolar disorder (BpO), and 47 offspring of community controls (CcO), 6 to 17 years old, were assessed with clinical and neuroimaging methods. Sixty-nine percent of the sample was reassessed at a 27.6-month (mean) follow-up. Cortical surface reconstruction was applied to measure cortical area and thickness using FreeSurfer; mixed-effects models were used to investigate cross-sectional and longitudinal differences in global and lobar morphologic measurements. RESULTS: The SzO group exhibited a cross-sectional decrease in global, parietal, and occipital lobe surface area compared with the CcO group, and in the occipital lobe compared with the BpO group. In the SzO group, global and parietal surface area values were inversely associated with attenuated positive and negative prodromal symptom scores. No cross-sectional differences in cortical thickness were observed. Division of the sample by pubertal status showed group-by-time interactions in the pubertal and postpubertal SzO subgroup, with less longitudinal decrease in cortical surface area and thickness than in the CcO and BpO subgroups, respectively. CONCLUSION: The SzO, but not the BpO, group was characterized by cross-sectional decreases in surface area, and this was associated with prodromal symptoms. Longitudinal changes in cortical morphology associated with risk for schizophrenia may be expressed differently according to developmental stage.