Identifying risk factors for predominant negative symptoms from early stages in schizophrenia: A longitudinal and sex-specific study in first-episode schizophrenia patients.

BACKGROUND: People with schizophrenia and predominant negative symptoms (PNS) present a different clinical and functional profile from those without such symptomatology. Few studies have examined the risk factors and the incidence of PNS in first-episode schizophrenia patients (FES) and differentiating by sex. This study aims to assess prevalence, demographic and clinical characteristics related to PNS from early stages and to study if there are sex-specific features in terms of developing PNS. METHODS: In a sample of 121 FES patients derived from a multicentre and naturalistic study, those who developed PNS at 12-months were identified. Environmental, clinical, functional, and cognitive ratings were examined longitudinally. Binary logistic regressions were applied to detect baseline risk factors for developing PNS at one-year follow-up. RESULTS: In the present FES cohort, 24.8% of the patients (n=30) developed PNS (20% of the women, 27.6% of the men). Compared to non-PNS (75.2%, n=91), at baseline, PNS group had more negative (t=-6.347; p<0.001) and depressive symptoms (t=-5.026; p<0.001), poorer premorbid adjustment (t=-2.791; p=0.006) and functional outcome (t=-2.649; p<0.001), more amotivation (t=-7.333; p<0.001), more expressivity alterations (t=-4.417; p<0.001), worse cognitive reserve (t=2.581; p<0.011), a lower estimated intelligent quotient (t=2.417; p=0.017), worse verbal memory (t=2.608; p=0.011), and worse fluency (t=2.614; p=0.010). Regressions showed that the premorbid adjustment was the main predictor of PNS in females (p=0.007; Exp(B)=1.106) while in males were a worse verbal memory performance (p=0.031; Exp(B)=0.989) and more alterations in the motivation domain (p=0.001; Exp(B)=1.607). CONCLUSIONS: A different baseline clinical profile and notable risk factors differences in the development of PNS between males and females were found. Results suggest that sex may be an important confounder in studies comparing schizophrenia patients with predominant and non-predominant negative symptomatology.

Obstetric complications and genetic risk for schizophrenia: Differential role of antenatal and perinatal events in first episode psychosis.

BACKGROUND: Obstetric complications (OCs) are key contributors to psychosis risk. However, it is unclear whether they increase psychosis vulnerability independently of genetic risk, in interaction with it, or are a manifestation of psychosis proneness. We examined the role of distinct types of OCs in terms of psychosis risk and tested whether they interact differently with genetic vulnerability, whilst accounting for other known environmental risk factors. STUDY DESIGN: 405 participants (219 first episode psychosis patients and 186 healthy volunteers) underwent a comprehensive assessment of OCs, measured using the Lewis-Murray scale and divided into complications of pregnancy, abnormalities of foetal growth and development, and complications of delivery. Participants were compared in terms of history of OCs, polygenic risk score for schizophrenia (PRS-SZ) and interactions between these. RESULTS: Both complications of pregnancy and abnormalities of foetal growth were significantly associated with case-control status (p = 0.02 and 0.03, respectively), whereas complications of delivery were not. PRS-SZ showed a significant association with psychosis (p = 0.04), but there were no significant interactions between genetic risk for schizophrenia and OCs, either when these were considered globally or separated based on their timeframe. CONCLUSIONS: We observed no significant interaction between genetic and obstetric vulnerability, yet distinct types of OCs may have a different impact on psychosis risk, based on their nature and timeframe. Examining their differential role might clarify their relative contributions to this risk.

Obstetric complications and clinical presentation in first episode of psychosis.

OBJECTIVE: Psychotic disorders exhibit a complex aetiology that combines genetic and environmental factors. Among the latter, obstetric complications (OCs) have been widely studied as risk factors, but it is not yet well understood how OCs relate to the heterogeneous presentations of psychotic disorders. We assessed the clinical phenotypes of individuals with a first episode of psychosis (FEP) in relation to the presence of OCs. METHODS: Two-hundred seventy-seven patients with an FEP were assessed for OCs using the Lewis-Murray scale, with data stratified into three subscales depending on the timing and the characteristics of the obstetric event, namely: complications of pregnancy, abnormal foetal growth and development and difficulties in delivery. We also considered other two groups: any complications during the pregnancy period and all OCs taken altogether. Patients were clinically evaluated with the Positive and Negative Syndrome Scale for schizophrenia. RESULTS: Total OCs and difficulties in delivery were related to more severe psychopathology, and this remained significant after co-varying for age, sex, traumatic experiences, antipsychotic dosage and cannabis use. CONCLUSIONS: Our results highlight the relevance of OCs for the clinical presentation of psychosis. Describing the timing of the OCs is essential in understanding the heterogeneity of the clinical presentation.

Negative symptoms and sex differences in first episode schizophrenia: What's their role in the functional outcome? A longitudinal study.

INTRODUCTION: Negative symptoms (NS) include asociality, avolition, anhedonia, alogia, and blunted affect and are linked to poor prognosis. It has been suggested that they reflect two different factors: diminished expression (EXP) (blunted affect and alogia) and amotivation/pleasure (MAP) (anhedonia, avolition, asociality). The aim of this article was to examine potential sex differences among first-episode schizophrenia (FES) patients and analyze sex-related predictors of two NS symptoms factors (EXP and MAP) and functional outcome. MATERIAL AND METHODS: Two hundred and twenty-three FES (71 females and 152 males) were included and evaluated at baseline, six-months and one-year. Repeated measures ANOVA was used to examine the effects of time and sex on NS and a multiple linear regression backward elimination was performed to predict NS factors (MAP-EXP) and functioning. RESULTS: Females showed fewer NS (p=0.031; Cohen's d=-0.312), especially those related to EXP (p=0.024; Cohen's d=-0.326) rather than MAP (p=0.086), than males. In both male and female group, worse premorbid adjustment and higher depressive symptoms made a significant contribution to the presence of higher deficits in EXP at one-year follow-up, while positive and depressive symptoms predicted alterations in MAP. Finally, in females, lower deficits in MAP and better premorbid adjustment predicted better functioning at one-year follow-up (R2=0.494; p<0.001), while only higher deficits in MAP predicted worse functioning in males (R2=0.088; p=0.012). CONCLUSIONS: Slightly sex differences have been found in this study. Our results lead us to consider that early interventions of NS, especially those focusing on motivation and pleasure symptoms, could improve functional outcomes.

Prefrontal abnormalities, executive dysfunction and symptoms severity are modulated by COMT Val158Met polymorphism in first episode psychosis.

INTRODUCTION: Core dysfunctions proposed for psychotic disorders include prefrontal cortex (PFC) dopaminergic hypoactivity, executive function (EF) deficits and reduced gray matter in the PFC. The Val variant of COMT Val158Met polymorphism is associated with reduced dopaminergic signaling in the PFC. However, it is unclear how COMT Val158Met modulates PFC gray matter reduction, EF deficits and symptom severity at the time of the first psychotic episode. METHODS: The effect of COMT on both EF performance and prefrontal volume (PFC-VOL) was tested in 158 first episode psychosis (FEP) patients and 141 healthy controls (HC) matched for age (range 9-35 years), sex, ethnicity, handedness and COMT Val158Met distribution. EF and PFC-VOL were compared between FEP and HC groups within each polymorphism status (Met/Met versus Val carriers) to assess whether COMT influenced diagnostic differences. Next, correlations between PFC-VOL and EF performance were computed, as well as between both variables and other clinical characteristics of interest (PANSS scores, PAS infancy and premorbid IQ) in the FEP sample. RESULTS: COMT influenced the diagnostic differences mainly in PFC-VOL, but also in EF performance. FEP-Val carriers showed lower EF scores and reduced PFC-VOL compared to the HC group but also poorer EF performance than FEP Met/Met. Poorer EF performance was associated with smaller PFC-VOL, and both were related to increased severity of negative symptoms, poorer premorbid adjustment, and lower estimated premorbid IQ in FEP patients. CONCLUSIONS: Our findings suggest that COMT Val158Met polymorphism might contribute to PFC-VOL reductions, executive dysfunctions and symptom severity in FEP patients.

Prefrontal abnormalities, executive dysfunction and symptoms severity are modulated by COMT Val158Met polymorphism in first episode psychosis / Modulación de alteraciones prefrontales por el polimorfismo COMT Val158Met en los primeros episodios psicóticos

Introduction: Core dysfunctions proposed for psychotic disorders include prefrontal cortex (PFC) dopaminergic hypoactivity, executive function (EF) deficits and reduced gray matter in the PFC. The Val variant of COMT Val158Met polymorphism is associated with reduced dopaminergic signaling in the PFC. However, it is unclear how COMT Val158Met modulates PFC gray matter reduction, EF deficits and symptom severity at the time of the first psychotic episode.Methods: The effect of COMT on both EF performance and prefrontal volume (PFC-VOL) was tested in 158 first episode psychosis (FEP) patients and 141 healthy controls (HC) matched for age (range 9–35 years), sex, ethnicity, handedness and COMT Val158Met distribution. EF and PFC-VOL were compared between FEP and HC groups within each polymorphism status (Met/Met versus Val carriers) to assess whether COMT influenced diagnostic differences. Next, correlations between PFC-VOL and EF performance were computed, as well as between both variables and other clinical characteristics of interest (PANSS scores, PAS infancy and premorbid IQ) in the FEP sample.Results: COMT influenced the diagnostic differences mainly in PFC-VOL, but also in EF performance. FEP-Val carriers showed lower EF scores and reduced PFC-VOL compared to the HC group but also poorer EF performance than FEP Met/Met. Poorer EF performance was associated with smaller PFC-VOL, and both were related to increased severity of negative symptoms, poorer premorbid adjustment, and lower estimated premorbid IQ in FEP patients.Conclusions: Our findings suggest that COMT Val158Met polymorphism might contribute to PFC-VOL reductions, executive dysfunctions and symptom severity in FEP patients. (AU)

Introducción: Algunas de las alteraciones descritas en los trastornos psicóticos incluyen una hipoactividad dopaminérgica en la corteza prefrontal (CPF), déficits en la función ejecutiva (FE) y reducción de la materia gris en la CPF. La variante Val del polimorfismo COMT Val158Met se asocia con una menor disponibilidad dopaminérgica en la CPF. Sin embargo, está aún pendiente de determinar la forma en la que COMT modula la materia gris de la CPF, la FE y la gravedad de los síntomas en el momento del primer episodio psicótico (PEP).Métodos: El efecto de COMT en el rendimiento de la FE y el volumen prefrontal (VOL-CPF) se evaluó en 158 pacientes con PEP y 141 controles sanos (CS) emparejados por edad (9-35 años), sexo, etnia y distribución de COMT. La FE y el VOL-CPF se compararon entre los grupos de PEP y CS, y en función de la variante alélica del polimorfismo (Met/Met versus portadores Val) para evaluar si COMT modula las diferencias diagnósticas. Además, se llevaron a cabo correlaciones entre FE y VOL-CPF, así como entre ambas variables y las puntuaciones en la PANSS, el ajuste premórbido y el CI premórbido.Resultados: COMT moduló las diferencias diagnósticas en VOL-CPF y el rendimiento de FE. Los PEP portadores de la variante Val presentaron menores puntuaciones en FE y reducción del VOL-CPF en comparación con el grupo CS, y menor rendimiento de FE que los PEP Met/Met. Un menor rendimiento en FE se asoció con un menor VOL-CPF, y ambas variables estaban relacionadas con un incremento en la gravedad de síntomas negativos, un peor ajuste premórbido y un menor CI premórbido en pacientes con PEP.Conclusiones: Nuestros hallazgos evidencian que el polimorfismo COMT Val158Met podría contribuir a la reducción del VOL-CPF, la disfunción ejecutiva y la gravedad de los síntomas en los pacientes con PEP. (AU)

Longitudinal Allometry of Sulcal Morphology in Health and Schizophrenia.

Scaling between subcomponents of folding and total brain volume (TBV) in healthy individuals (HIs) is allometric. It is unclear whether this is true in schizophrenia (SZ) or first-episode psychosis (FEP). This study confirmed normative allometric scaling norms in HIs using discovery and replication samples. Cross-sectional and longitudinal diagnostic differences in folding subcomponents were then assessed using an allometric framework. Structural imaging from a longitudinal (Sample 1: HI and SZ, nHI Baseline = 298, nSZ Baseline = 169, nHI Follow-up = 293, nSZ Follow-up = 168, totaling 1087 images, all individuals ≥ 2 images, age 16-69 years) and a cross-sectional sample (Sample 2: nHI = 61 and nFEP = 89, age 10-30 years), all human males and females, is leveraged to calculate global folding and its nested subcomponents: sulcation index (SI, total sulcal/cortical hull area) and determinants of sulcal area: sulcal length and sulcal depth. Scaling of SI, sulcal area, and sulcal length with TBV in SZ and FEP was allometric and did not differ from HIs. Longitudinal age trajectories demonstrated steeper loss of SI and sulcal area through adulthood in SZ. Longitudinal allometric analysis revealed that both annual change in SI and sulcal area was significantly stronger related to change in TBV in SZ compared with HIs. Our results detail the first evidence of the disproportionate contribution of changes in SI and sulcal area to TBV changes in SZ. Longitudinal allometric analysis of sulcal morphology provides deeper insight into lifespan trajectories of cortical folding in SZ.SIGNIFICANCE STATEMENT Psychotic disorders are associated with deficits in cortical folding and brain size, but we lack knowledge of how these two morphometric features are related. We leverage cross-sectional and longitudinal samples in which we decompose folding into a set of nested subcomponents: sulcal and hull area, and sulcal depth and length. We reveal that, in both schizophrenia and first-episode psychosis, (1) scaling of subcomponents with brain size is different from expected scaling laws and (2) caution is warranted when interpreting results from traditional methods for brain size correction. Longitudinal allometric scaling points to loss of sulcal area as a principal contributor to loss of brain size in schizophrenia. These findings advance the understanding of cortical folding atypicalities in psychotic disorders.

Cortical thinning over two years after first-episode psychosis depends on age of onset.

First-episode psychosis (FEP) patients show structural brain abnormalities at the first episode. Whether the cortical changes that follow a FEP are progressive and whether age at onset modulates these changes remains unclear. This is a multicenter MRI study in a deeply phenotyped sample of 74 FEP patients with a wide age range at onset (15-35 years) and 64 neurotypical healthy controls (HC). All participants underwent two MRI scans with a 2-year follow-up interval. We computed the longitudinal percentage of change (PC) for cortical thickness (CT), surface area (CSA) and volume (CV) for frontal, temporal, parietal and occipital lobes. We used general linear models to assess group differences in PC as a function of age at FEP. We conducted post-hoc analyses for metrics where PC differed as a function of age at onset. We found a significant age-by-diagnosis interaction effect for PC of temporal lobe CT (d = 0.54; p = 002). In a post-hoc-analysis, adolescent-onset (≤19 y) FEP showed more severe longitudinal cortical thinning in the temporal lobe than adolescent HC. We did not find this difference in adult-onset FEP compared to adult HC. Our study suggests that, in individuals with psychosis, CT changes that follow the FEP are dependent on the age at first episode, with those with an earlier onset showing more pronounced cortical thinning in the temporal lobe.

Early signs of autism in infants whose mothers suffered from a threatened preterm labour: a 30-month prospective follow-up study.

Infants born after a threatened preterm labour (TPL infants) are at high risk of autism spectrum disorder (ASD). Studying this population may provide insight on the pathophysiological underpinnings of this condition. This study aimed to (i) ascertain the presence and autistic symptom load in TPL infants aged age 30 months relative to non-TPL infants, regardless of preterm birth; (ii) explore the association between early (at 6 months) psychomotor development and temperament features with the autistic symptom load of TPL infants at age 30 months and (iii) examine the association among perinatal risk factors for ASD development with the autistic symptom load of TPL infants at age 30 months. A group of 111 mother-infant pairs recruited at TPL diagnosis and a group of 47 healthy mother-infant controls completed the follow-up. Irrespective of preterm birth, TPL infants showed higher autistic symptom load at age 30 months than non-TPL infants. TPL infants presented poorer communication and problem-solving skills, reduced smiling and laughter, and greater vocal reactivity at age 6 months, predicting higher autistic symptom load at age 30 months. Higher levels of anxiety symptoms in TPL mothers after a TPL diagnosis also predicted higher autistic symptom load for the infants at age 30 months. These results suggest that TPL infants may be an undescribed cluster, with features that differentiate them from other "at-risk" populations. These findings support the need for routine assessment of TPL infants and screening of anxiety symptoms in mothers.

Cognitive clusters in first-episode psychosis.

Impairments in a broad range of cognitive domains have been consistently reported in some individuals with first-episode psychosis (FEP). Cognitive deficits can be observed during the prodromal stage. However, the course of cognitive deficits is still unclear. The aim of this study was to identify cognitive subgroups over time and to compare their sociodemographic, clinical and functional profiles. A total of 114 patients with Schizophrenia Spectrum Disorders were included in the present study. We assessed subjects through psychiatric scales and eight neuropsychological tests at baseline and at two-year follow-up visit. We performed the Partition Around Medoids algorithm with all cognitive variables. Furthermore, we performed a logistic regression to identify the predictors related to the different cognitive clusters at follow-up. Two distinct subgroups were found: the first cluster characterized by cognitive impairment and a second cluster had relatively intact cognition in comparison with norms. Up to 54.7% of patients with cognitive deficits at baseline tended to improve during the first two years of treatment. Patients with intact cognition at follow-up had a higher socioeconomic status, later age of onset, lower negative symptoms and a higher cognitive reserve (CR) at baseline. CR and age of onset were the baseline variables that predicted cognitive impairment. This research allows us to obtain a better understanding of the heterogeneous profile of psychotic disorders. Identifying the characteristics of patients who will present a cognitive impairment could improve early detection and intervention. These results suggest that enhancing CR could contribute to improving the course of the illness.

Impact of previous tobacco use with or without cannabis on first psychotic experiences in patients with first-episode psychosis.

OBJECTIVE: There is high prevalence of cigarette smoking in individuals with first-episode psychosis (FEP) prior to psychosis onset. The purpose of the study was to determine the impact of previous tobacco use with or without cannabis on first psychotic experiences in FEP and the impact of this use on age of onset of symptoms, including prodromes. METHODS: Retrospective analyses from the naturalistic, longitudinal, multicentre, "Phenotype-Genotype and Environmental Interaction. Application of a Predictive Model in First Psychotic Episodes (PEPs)" Study. The authors analysed sociodemographic/clinical data of 284 FEP patients and 231 matched healthy controls, and evaluated first psychotic experiences of patients using the Symptom Onset in Schizophrenia Inventory. RESULTS: FEP patients had significantly higher prevalence of tobacco, cannabis, and cocaine use than controls. The FEP group with tobacco use only prior to onset (N = 56) had more sleep disturbances (42.9% vs 18.8%, P = 0.003) and lower prevalence of negative symptoms, specifically social withdrawal (33.9% vs 58%, P = 0.007) than FEP with no substance use (N = 70), as well as lower prevalence of ideas of reference (80.4% vs 92.4%, P = 0.015), perceptual abnormalities (46.4% vs 67.4%, P = 0.006), hallucinations (55.4% vs 71.5%, P = 0.029), and disorganised thinking (41.1% vs 61.1%, P = 0.010) than FEP group with previous tobacco and cannabis use (N = 144). FEP patients with cannabis and tobacco use had lower age at first prodromal or psychotic symptom (mean = 23.73 years [SD = 5.09]) versus those with tobacco use only (mean = 26.21 [SD = 4.80]) (P = 0.011). CONCLUSIONS: The use of tobacco alone was not related to earlier age of onset of a first psychotic experience, but the clinical profile of FEP patients is different depending on previous tobacco use with or without cannabis.

The role of depression in the prediction of a "late" remission in first-episode psychosis: An analysis of the OPTiMiSE study.

OBJECTIVE: The identification of predictors of psychosis remission could guide early clinical decision-making for treatment of first-episode schizophrenia (FES). METHODS: We analyzed two non-independent subsamples of patients with FES ages 18-40 years from the OPTiMiSE study dataset to investigate the demographic and clinical factors that might help to differentiate "late" remitters (i.e., not in remission at week 2 or 4, but achieving remission within a 10-week follow-up period) from non-remitters within the same period. RESULTS: Subsample 1 included 216 individuals (55 females, mean age 25.9 years) treated with amisulpride in an open-label design who were not in remission at week 2. Early symptomatic response between baseline and week 2 (odds ratio (OR) = 4.186, 95% confidence interval (CI) = 2.082-8.416, p < 0.001) and older age (OR = 1.081, 95% CI = 1.026-1.138, p = 0.003) were the only variables significantly associated with a higher probability of psychosis remission at week 4. Subsample 2 was composed of the 72 participants (19 females, mean age 25.1 years) who were not in remission at week 4 and completed a 6-week double-blind randomized trial comparing continuation of amisulpride with switch to olanzapine. Depression at baseline (as measured with the Calgary Depression Scale for Schizophrenia) was significantly associated with a nearly 3-fold lower likelihood of psychosis remission during the 10-week follow-up (hazard ratio = 2.865, 95% CI = 1.187-6.916, p = 0.019). CONCLUSION: Our results reinforce the importance of assessing depressive symptoms in people with FES and support the relevance of an early response (as early as 2 weeks) as a predictor of clinical outcome in this population. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier: NCT01248195, https://clinicaltrials.gov/ct2/show/NCT01248195.

The effect of family environment and psychiatric family history on psychosocial functioning in first-episode psychosis at baseline and after 2 years.

The aim of the present study was to evaluate the contribution of family environment styles and psychiatric family history on functioning of patients presenting first-episode psychosis (FEP). Patients with FEP and healthy controls (HC) were assessed at baseline and after 2 years. The Functional Assessment Short Test (FAST) was used to assess functional outcome and the Family Environment Scale (FES) to evaluate family environment. Linear regressions evaluated the effect that family environment exerts on functioning at baseline and at 2-year follow-up, when FEP patients were diagnosed according to non-affective (NA-PSYCH) or affective psychoses (A-PSYCH). The influence of a positive parents' psychiatric history on functioning was evaluated through one-way between-groups analysis of covariance (ANCOVA) models, after controlling for family environmental styles. At baseline, FEP patients presented moderate functioning impairment, significantly worse than HC (28.65±16.17 versus 3.25±7.92; p<0.001, g = 1.91). At 2-year follow-up, the functioning of NA-PSYCH patients was significantly worse than in A-PSYCH (19.92±14.83 versus 12.46±14.86; p = 0.020, g = 0.50). No specific family environment style was associated with functioning in FEP patients and HC. On the contrary, a positive psychiatric father's history influenced functioning of FEP patients. After 2 years, worse functioning in NA-PSYCH patients was associated with lower rates of active-recreational and achievement orientated family environment and with higher rates of moral-religious emphasis and control. In A-PSYCH, worse functioning was associated with higher rates of conflict in the family. Both family environment and psychiatric history influence psychosocial functioning, with important implications for early interventions, that should involve both patients and caregivers.

The functioning assessment short test (FAST) applied to first-episode psychosis: Psychometric properties and severity thresholds.

Functional impairment is a defining feature of psychotic disorders. The Functional Assessment Short Test (FAST) is one of the most widely used instruments to measure psychosocial functioning. However, cut-offs of impairment have been well-established for bipolar disorders, but not for other clinical populations. This study aims to analyse psychometric properties of the FAST and establish their corresponding cut-off values for the different severity gradations in a first-episode of non-affective psychosis (FEP) patients. Global Assessment Functioning (GAF) and FAST ratings from 212 non-affective FEP and 204 healthy controls were analyzed. The psychometric properties of FAST (internal consistency, concurrent validity, discriminant validity, factorial analyses and sensitivity to change) were analyzed. The severity gradations of the FAST were defined by the congruence between two grading methods: linear regression analysis (LRA) and percentiles. The FAST showed strong psychometric properties. LRA with the GAF scores yielded the following equation: GAFscore= 80.83 - 0.639*FASTscore. The FAST ranges in non-affective FEP patients derived from LRA and percentiles, were as follows: 0-9 (No impairment); 10-19 (Minimal impairment); 20-34 (Mild impairment); 35-45 (Moderate impairment); 46-72 (Severe impairment). Patients with no functional impairment had a higher socioeconomic status, fewer depressive and negative symptoms, lower severity of illness and higher cognitive reserve level than the others groups. In conclusion, the FAST shows optimal psychometric properties which corroborate its applicability in FEP populations. It is a well-demonstrated valid instrument and the present cut-off scores could be implemented in clinical and research practice to assess properly the psychosocial functional outcome of non-affective FEP populations.

Study of the pathophysiological mechanisms associated with the onset and course of neurodevelopmental disorders in preterm infants (the PeriSTRESS-PremTEA study): Rationale, objectives, design and sample description. / Estudio de los mecanismos fisiopatológicos asociados al inicio y curso de los trastornos del neurodesarrollo en prematuros (estudio PeriSTRESS-PremTEA): justificación, objetivos, diseño y descripción de la muestra.

BACKGROUND: There are few studies exploring the pathophysiological pathways that may condition differentially the emergence/course of neurodevelopmental disorders (ND) in very preterm and extremely preterm newborns (VPTN/EPTN). Furthermore, there are no established biological markers predictive of ND in this population. The aim of this study is four-fold: in two cohorts of VPTN/EPTN (i) to characterize the emergence/course of ND up to corrected-age 6 years, (ii) to identify those factors (from prenatal stages up to age 6 years) that explain the interindividual differences related to emergence/course of ND, (iii) to identify in the first hours/days of life a urinary metabolomic biomarker profile predictive of ND, and (iv) to determine longitudinally variations in DNA methylation patterns predictive of ND. METHODS: Observational, longitudinal, prospective, six-year follow-up, multicentre collaborative study. Two cohorts are being recruited: the PeriSTRESS-Valencia-cohort (n=26 VPTN, 18 EPTN, and 122 born-at-term controls), and the PremTEA-Madrid-cohort (n=49 EPTN and n=29 controls). RESULTS: We describe the rationale, objectives and design of the PeriSTRESS-PremTEA project and show a description at birth of the recruited samples. CONCLUSIONS: The PeriSTRESS-PremTEA project could help improve early identification of clinical, environmental and biological variables involved in the physiopathology of ND in VPTN/EPTN. It could also help to improve the early identification of non-invasive ND biomarkers in this population. This may allow early ND detection as well as early and personalised intervention for these children.

Identifying clinical clusters with distinct trajectories in first-episode psychosis through an unsupervised machine learning technique.

The extreme variability in symptom presentation reveals that individuals diagnosed with a first-episode psychosis (FEP) may encompass different sub-populations with potentially different illness courses and, hence, different treatment needs. Previous studies have shown that sociodemographic and family environment factors are associated with more unfavorable symptom trajectories. The aim of this study was to examine the dimensional structure of symptoms and to identify individuals' trajectories at early stage of illness and potential risk factors associated with poor outcomes at follow-up in non-affective FEP. One hundred and forty-four non-affective FEP patients were assessed at baseline and at 2-year follow-up. A Principal component analysis has been conducted to identify dimensions, then an unsupervised machine learning technique (fuzzy clustering) was performed to identify clinical subgroups of patients. Six symptom factors were extracted (positive, negative, depressive, anxiety, disorganization and somatic/cognitive). Three distinct clinical clusters were determined at baseline: mild; negative and moderate; and positive and severe symptoms, and five at follow-up: minimal; mild; moderate; negative and depressive; and severe symptoms. Receiving a low-dose antipsychotic, having a more severe depressive symptomatology and a positive family history for psychiatric disorders were risk factors for poor recovery, whilst having a high cognitive reserve and better premorbid adjustment may confer a better prognosis. The current study provided a better understanding of the heterogeneous profile of FEP. Early identification of patients who could likely present poor outcomes may be an initial step for the development of targeted interventions to improve illness trajectories and preserve psychosocial functioning.

The longitudinal effect of antipsychotic burden on psychosocial functioning in first-episode psychosis patients: the role of verbal memory.

BACKGROUND: Previous literature supports antipsychotics' (AP) efficacy in acute first-episode psychosis (FEP) in terms of symptomatology and functioning but also a cognitive detrimental effect. However, regarding functional recovery in stabilised patients, these effects are not clear. Therefore, the main aim of this study is to investigate dopaminergic/anticholinergic burden of (AP) on psychosocial functioning in FEP. We also examined whether cognitive impairment may mediate these effects on functioning. METHODS: A total of 157 FEP participants were assessed at study entry, and at 2 months and 2 years after remission of the acute episode. The primary outcomes were social functioning as measured by the functioning assessment short test (FAST). Cognitive domains were assessed as potential mediators. Dopaminergic and anticholinergic AP burden on 2-year psychosocial functioning [measured with chlorpromazine (CPZ) and drug burden index] were independent variables. Secondary outcomes were clinical and socio-demographic variables. RESULTS: Mediation analysis found a statistical but not meaningful contribution of dopaminergic receptor blockade burden to worse functioning mediated by cognition (for every 600 CPZ equivalent points, 2-year FAST score increased 1.38 points). Regarding verbal memory and attention, there was an indirect effect of CPZ burden on FAST (b = 0.0045, 95% CI 0.0011-0.0091) and (b = 0.0026, 95% CI 0.0001-0.0006) respectively. However, only verbal memory post hoc analyses showed a significant indirect effect (b = 0.009, 95% CI 0.033-0.0151) adding premorbid IQ as covariate. We did not find significant results for anticholinergic burden. CONCLUSION: CPZ dose effect over functioning is mediated by verbal memory but this association appears barely relevant.

[Patient care, right to information and consent for minors in situations of parental conflict. Clinical guidelines in the context of Spanish legislation]. / Atención a menores con progenitores en conflicto en materia de información y consentimiento relativos a la salud de los hijos. Protocolo asistencial en el contexto de la legislación vigente.

Among the main social and legislative changes as regards family matters that have taken place in Spain in the last few years, are included: (i) the gradual increase in legal disputes between parents, and (ii) the introduction of Law 26/2015 on Child Protection, which modified Law 41/2002 on the Freedom of the Patient. These searched for a balance between the rights of minors and the powers of the parents, particularly when the former had not reached 16 years or had sufficient maturity or, having reached it, the decision puts their life or health at severe risk. Likewise, it has led to a jurisprudence that determines that, for any minor, there are particularly sensitive, "special" or "important" health care actions, such as psychotherapy or surgical treatments, which require, with exceptions, the consent of both parents for it to be carried out. All this, however, subject to the discretion of the doctor responsible, who must always look after the best interests of the minor. For this reason, healthcare for minors, occasionally, lead to complex conflicts as regards information and consent by the parents, particularly when they do not agree. A review is presented on the current legislative framework and the main legal concepts that regulate the healthcare of minors as regards information and consent relative to health, as well a healthcare protocol for the care of minors in situations of conflict between parents, developed in the Gregorio Marañón Hospital of Madrid, and endorsed by the Official Medical Collegiate of Madrid.

Exploring Risk and Resilient Profiles for Functional Impairment and Baseline Predictors in a 2-Year Follow-Up First-Episode Psychosis Cohort Using Latent Class Growth Analysis.

Being able to predict functional outcomes after First-Episode Psychosis (FEP) is a major goal in psychiatry. Thus, we aimed to identify trajectories of psychosocial functioning in a FEP cohort followed-up for 2 years in order to find premorbid/baseline predictors for each trajectory. Additionally, we explored diagnosis distribution within the different trajectories. A total of 261 adults with FEP were included. Latent class growth analysis identified four distinct trajectories: Mild impairment-Improving trajectory (Mi-I) (38.31% of the sample), Moderate impairment-Stable trajectory (Mo-S) (18.39%), Severe impairment-Improving trajectory (Se-I) (12.26%), and Severe impairment-Stable trajectory (Se-S) (31.03%). Participants in the Mi-I trajectory were more likely to have higher parental socioeconomic status, less severe baseline depressive and negative symptoms, and better premorbid adjustment than individuals in the Se-S trajectory. Participants in the Se-I trajectory were more likely to have better baseline verbal learning and memory and better premorbid adjustment than those in the Se-S trajectory. Lower baseline positive symptoms predicted a Mo-S trajectory vs. Se-S trajectory. Diagnoses of Bipolar disorder and Other psychoses were more prevalent among individuals falling into Mi-I trajectory. Our findings suggest four distinct trajectories of psychosocial functioning after FEP. We also identified social, clinical, and cognitive factors associated with more resilient trajectories, thus providing insights for early interventions targeting psychosocial functioning.