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The validation of nosological diagnoses in psychiatry remains a conundrum. Leonhard's (1979) nosology seems to be one of the few acceptable alternative categorical models to current DSM/ICD systems. We aimed to empirically validate Leonhard's four classes of psychoses: systematic schizophrenia (SSch), unsystematic (USch), cycloid psychosis (Cyclo), and manic-depressive illness (MDI) using a comprehensive set of explanatory validators. 243 patients with first-episode psychosis were followed between 10 and 31 years. A wide-ranging assessment was carried out by collecting data on antecedent, illness-related, concurrent, response to treatment, neuromotor abnormalities, and cognitive impairment variables. Compared with USch, Cyclo, and MDI, SSch displayed a pattern of impairments significantly larger across the seven blocks of explanatory variables. There were no significant differences between Cyclo and MDI in explanatory variables. Except for the majority of illness-onset features, USch displayed more substantial abnormalities in the explanatory variables than Cyclo and MDI. SSch and MDI showed higher percentages of correctly classified patients than USch and Cyclo in linear discriminant analyses. Partial validation of Leonhard's classification was found. SSch showed differences in explanatory variables with respect to Cyclo and MDI. USch showed also significant differences in explanatory variables regarding Cyclo and MDI, although with a lower strength than SSch. There was strong empirical evidence of the separation between both Leonhard's schizophrenia subtypes; however, the distinction between the Cyclo and MDI groups was not empirically supported. A mild to moderate discriminative ability between Leonhard's subtypes on the basis of explanatory blocks of variables was observed.

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Cognitive intraindividual variability (IIV) refers to fluctuations in performance across tasks (i.e. dispersion) or in a single task on multiple occasions (i.e. inconsistency). Little is known about IIV in patients with first-episode psychosis (FEP). We aimed to explore the association between IIV and both global cognitive performance and psychosocial functioning in a sample of 103 FEP patients. Patients were recruited at discharge from the PEPsNa program, a FEP follow-up intervention program lasting 24 months. The Social and Occupational Functioning Scale (SOFAS) and the Cognitive Assessment Interview (CAI-Sp) were employed for assessing psychosocial functioning. Cognitive assessments were performed using the MATRICS Cognitive Assessment Battery (MCCB), and the variability in the cognitive functions assessed with the MCCB was used to calculate the IIV. Significant correlations were obtained between IIV and global MCCB scores, the CAI-Sp and the SOFAS. We found significant differences in psychosocial functioning and cognitive performance between patients with high and low IIV. A higher IIV in FEP patients was related both to worse psychosocial functioning and worse global cognitive performance. Unlike global cognitive performance, IIV was not related to clinical characteristics, suggesting that it could be an indicator of cognitive impairment even in the absence of global impairment.

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BACKGROUND: Consistent evidence supports the involvement of genetic and environmental factors, and their interactions, in the etiology of psychosis. First-episode psychosis (FEP) comprises a group of disorders that show great clinical and long-term outcome heterogeneity, and the extent to which genetic, familial and environmental factors account for predicting the long-term outcome in FEP patients remains scarcely known. METHODS: The SEGPEPs is an inception cohort study of 243 first-admission patients with FEP who were followed-up for a mean of 20.9 years. FEP patients were thoroughly evaluated by standardized instruments, with 164 patients providing DNA. Aggregate scores estimated in large populations for polygenic risk score (PRS-Sz), exposome risk score (ERS-Sz) and familial load score for schizophrenia (FLS-Sz) were ascertained. Long-term functioning was assessed by means of the Social and Occupational Functioning Assessment Scale (SOFAS). The relative excess risk due to interaction (RERI) was used as a standard method to estimate the effect of interaction of risk factors. RESULTS: Our results showed that a high FLS-Sz gave greater explanatory capacity for long-term outcome, followed by the ERS-Sz and then the PRS-Sz. The PRS-Sz did not discriminate significantly between recovered and non-recovered FEP patients in the long term. No significant interaction between the PRS-Sz, ERS-Sz or FLS-Sz regarding the long-term functioning of FEP patients was found. CONCLUSIONS: Our results support an additive model of familial antecedents of schizophrenia, environmental risk factors and polygenic risk factors as contributors to a poor long-term functional outcome for FEP patients.

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Little is known about long-term outcomes of the first episode of psychosis (FEP) other than in the symptomatic domain. We hypothesised that cognitive impairment is associated with poorer multi-domain outcomes at a long-term follow-up of FEP patients. We followed-up 172 FEP patients for a mean of 20.3 years. Ten outcome dimensions were assessed (symptomatic, functional and personal recovery, social disadvantage, physical health, suicide attempts, number of episodes, current drug use, chlorpromazine equivalent doses (CPZ), and schizophrenia/schizoaffective disorder final diagnosis). Cognition was assessed at follow-up. Processing speed and verbal memory deficits showed significant associations with poor outcomes on symptomatic, social functioning, social disadvantage, higher number of episodes, and higher CPZ. Significant associations were found between visual memory impairments were significantly associated with low symptomatic and functional recovery, between attentional deficits and a final diagnosis of schizophrenia/schizoaffective disorder, and between social cognition deficits and poor personal recovery.Lower cognitive global scores were significantly associated with all outcome dimensions except for drug abuse and physical status. Using multiple outcome dimensions allowed for the inclusion of the patients' perspective and other commonly neglected outcome measures. Taken together, cognitive impairment in FEP patients is strongly related to poor performance on several outcome dimensions beyond symptomatic remission.

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BACKGROUND: Schizophrenia-spectrum disorders (SSD) and Autism spectrum disorders (ASD) are neurodevelopmental disorders that share clinical, cognitive, and genetic characteristics, as well as particular white matter (WM) abnormalities. In this study, we aimed to investigate the role of a set of oligodendrocyte/myelin-related (OMR) genes and their epistatic effect on the risk for SSD and ASD. METHODS: We examined 108 SNPs in a set of 22 OMR genes in 1749 subjects divided into three independent samples (187 SSD trios, 915 SSD cases/control, and 91 ASD trios). Genetic association and gene-gene interaction analyses were conducted with PLINK and MB-MDR, and permutation procedures were implemented in both. RESULTS: Some OMR genes showed an association trend with SSD, while after correction, the ones that remained significantly associated were MBP, ERBB3, and AKT1. Significant gene-gene interactions were found between (i) NRG1*MBP (perm p-value = 0.002) in the SSD trios sample, (ii) ERBB3*AKT1 (perm p-value = 0.001) in the SSD case-control sample, and (iii) ERBB3*QKI (perm p-value = 0.0006) in the ASD trios sample. DISCUSSION: Our results suggest the implication of OMR genes in the risk for both SSD and ASD and highlight the role of NRG1 and ERBB genes. These findings are in line with the previous evidence and may suggest pathophysiological mechanisms related to NRG1/ERBBs signalling in these disorders.

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OBJETIVOS: Determinar la asociación entre el consumo de sustancias y características de salud sexual y reproductiva de mujeres jóvenes en Chile. MÉTODOS: Estudio transversal analítico en mujeres entre 15 a 24 años. Se formaron 3 grupos: Sin consumo de sustancias (SCS), Consumo no problemático de sustancias (CNPS) y Consumo problemático de sustancias (CPS). Se realizó análisis descriptivo y de asociación entre las variables. Se ajustaron modelos de regresión logística múltiple y ordinal múltiple. RESULTADOS: Muestra de 2.589 jóvenes, el 37,8% correspondió al grupo SCS, 46,3% al grupo CSNP y 15,9% al grupo CPS. En promedio la edad de inicio de actividad sexual fue menor en el grupo CPS (15,9 años p = 0,001) mostrando mayor porcentajes de sexo oral, anal, no uno de condón, relaciones sexuales con parejas menos estables, mayor número de parejas sexuales y violencia en la pareja, (p =0,001). En este grupo se incrementa 5,84 el riesgo de tener la última relación sexual con pareja menos estable (IC95%: 3,90 - 12,01) y 8,35 veces el riesgo de tener 2 o más parejas sexuales (últimos 12 meses) (IC95%: 5,35 - 16,34). En el grupo CNPS se incrementa 1,11 veces el riesgo de tener la última relación sexual con pareja menos estable (IC95%: 1,43 - 3,12), 1,01 veces tener 2 y más parejas sexuales (últimos 12 meses) (IC95%: 1,20 - 3,36). CONCLUSIONES: Reconociéndose que la sexualidad es multifactorial, las mujeres con consumo de sustancias viven situaciones que facilitan riesgos para su salud sexual. El consumo en mujeres jóvenes es un problema de salud pública que presenta desafíos para su abordaje.

OBJECTIVES: To determine the association between substance use and characteristics of sexual and reproductive health of young women in Chile. METHODS: Analytical cross-sectional study in women between 15 and 24 years. Three groups were formed: No substance use (SCS), Non-problematic substance use (CNPS) and Problem substance use (CPS). Descriptive and association analysis was performed between the variables. Multiple logistic regression and multiple ordinal models were adjusted. RESULTS: Sample of 2,589 young people, 37.8% corresponded to the SCS group, 46.3% to the CSNP group and 15.9% to the CPS group. On average the age of onset of sexual activity was lower in the CPS group (15.9 years p = 0.001) showing higher percentages of oral, anal sex, not a condom, sex with less stable partners, greater number of sexual partners and violence in the couple, (p = 0.001). In this group the risk of having the last sexual relationship with a less stable partner is increased 5.84 (95% CI: 3.90 - 12.01) and 8.35 times the risk of having 2 or more sexual partners (last 12 months) (95% CI: 5.35-16.34). In the CNPS group the risk of having the last sexual relationship with a less stable partner is increased 1.11 times (95% CI: 1.43 - 3.12), 1.01 times having 2 and more sexual partners (last 12 months) (95% CI: 1.20-3.36). CONCLUSIONS: Recognizing that sexuality is multifactorial, women with substance use experience situations that facilitate risks to their sexual health. Consumption in young women is a public health problem that presents challenges for its approach.

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BACKGROUND: Depression, anxiety and somatoform disorders are all more prevalent in women than in men. However, specific biological mechanisms contributing to such sex differences remain unknown. Serotonergic pathways are involved in mood and behavior regulation and thus have been suggested to be altered in several psychiatric disorders. The serotonin transporter (SERT), encoded by SLC6A4 gene, has received major attention due to its crucial role in serotonergic transmission. METHODS: 148 monozygotic twin subjects were assessed for (i) lifetime categorical diagnosis of anxious-depressive disorders, following SCID-I-based DSM-IV criteria, and (ii) current psychiatric symptomatology, from a dimensional approach, by means of the Brief Symptom Inventory (BSI). SLC6A4 gene methylation was analyzed by means of Infinium HumanMethylation450 in a subset of the sample. CpG-specific methylation at the promoter region of SLC6A4 gene was further analyzed by means of pyrosequencing technology in the total sample. RESULTS: SLC6A4 methylation was found to be significantly higher in women when compared to men independent of DSM-IV diagnosis. SLC6A4 methylation was further associated with the BSI-derived somatization dimension. CONCLUSIONS: Female hypermethylation of a discrete region located within SLC6A4 promoter region could underlie differential SERT expression in women when compared to men and could be one of the causative mechanisms by which women exhibit increased prevalence of somatic symptoms.

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Zoonotic transmission of Salmonella infections causes an estimated 11% of salmonellosis annually in the United States. This report describes the epidemiologic, traceback and laboratory investigations conducted in the United States as part of four multistate outbreaks of Salmonella infections linked to small turtles. Salmonella isolates indistinguishable from the outbreak strains were isolated from a total of 143 ill people in the United States, pet turtles, and pond water samples collected from turtle farm A, as well as ill people from Chile and Luxembourg. Almost half (45%) of infections occurred in children aged <5 years, underscoring the importance of the Centers for Disease Control and Prevention recommendation to keep pet turtles and other reptiles out of homes and childcare settings with young children. Although only 43% of the ill people who reported turtle exposure provided purchase information, most small turtles were purchased from flea markets or street vendors, which made it difficult to locate the vendor, trace the turtles to a farm of origin, provide education and enforce the United States federal ban on the sale and distribution of small turtles. These outbreaks highlight the importance of improving public awareness and education about the risk of Salmonella from small turtles not only in the United States but also worldwide.

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BACKGROUND: The interest in studying gene-gene interactions is increasing for psychiatric diseases such as schizophrenia-spectrum disorders (SSD), where multiple genes are involved. Dysbindin-1 (DTNBP1) and Neuritin-1 (NRN1) genes have been previously associated with SSD and both are involved in synaptic plasticity. We aimed to study whether these genes show an epistatic effect on the risk for SSD. METHODS: The sample comprised 388 SSD patients and 397 healthy subjects. Interaction was tested between: (i) three DTNBP1 SNPs (rs2619537, rs2743864, rs1047631) related to changes in gene expression; and (ii) an haplotype in NRN1 previously associated with the risk for SSD (rs645649-rs582262: HAP-risk C-C). RESULTS: An interaction between DTNBP1 rs2743864 and NRN1 HAP-risk was detected by using the model based multifactor dimensionality reduction (MB-MDR) approach (P=0.0049, after permutation procedure), meaning that the risk for SSD is significantly higher in those subjects carrying both the A allele of rs2743864 and the HAP-risk C-C. This interaction was confirmed by using a logistic regression model (P=0.033, OR (95%CI)=2.699 (1.08-6.71), R2=0.162). DISCUSSION: Our results suggest that DTNBP1 and NRN1 genes show a joint effect on the risk for SSD. Although the precise mechanism underlying this effect is unclear, the fact that these genes have been involved in synaptic maturation, connectivity and glutamate signalling suggests that our findings could be of value as a link to the schizophrenia aetiology.

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INTRODUCTION: This study explored schizotypy as a familial liability marker for schizophrenia-spectrum disorders (SSD) by examining: 1) the aggregation of schizotypy in families with a SSD patient, 2) whether familial resemblance of schizotypy is associated with ridge dissociations (RD), another SSD liability marker, 3) whether schizotypy aggregation patterns influence patients' psychopathology. METHODS: The sample comprised 30 SSD patients and 82 healthy first-degree relatives. Schizotypy was assessed using the Structured Interview for Schizotypy-Revised (SIS-R). Patients' psychopathology was evaluated using the Comprehensive Assessment of Symptoms and History (CASH). RD were identified as anomalies of the dermal ridge junction. Familiality of SIS-R was investigated using a linear mixed model (LMM) and its strength was assessed using an intraclass correlation coefficient (ICC). Another LMM using the absolute differences in SIS-R scores between all possible pairs of relatives as the dependent variable was fitted to obtain an intra-family resemblance score, a family-specific indicator of resemblance of SIS-R scores within each family. RESULTS: 1) Schizotypy was familial (ICC = 0.30); families with high resemblance displayed low schizotypy, whereas families with low resemblance included at least one healthy relative with high schizotypy (p < 0.001). 2) Relatives with RD had higher SIS-R scores (p = 0.018) and belonged to families with discordant schizotypy scores among members (p < 0.001). 3) Patients from high schizotypy families showed more severe disorganized symptoms at the psychotic episode (p = 0.035) and 1 year later (p = 0.011). CONCLUSIONS: Schizotypy is a marker of vulnerability for SSD that runs within a subgroup of families. The schizotypy familial aggregation pattern correlates with RD in relatives and with patients' psychopathology.

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BACKGROUND: Delusional disorder (DD) is an under-researched condition and its relationship to schizophrenia (SZ) controversial. This study aimed to further characterize DD and to examine multi-domain evidence for the distinction between DD and SZ. METHOD: Using univariate analyses we examined 146 subjects with DD, 114 subjects with paranoid SZ and 244 subjects with non-paranoid SZ on 52 characteristics from several domains including demographics, risk factors, premorbid features, illness characteristics, index episode features, delusional-related features, response to treatment and outcome. In a further step, we searched for independent associations of the examined characteristics with DD v. SZ. RESULTS: Univariate analyses showed that DD differed from either form of SZ in 40 characteristics, the pattern of findings indicated that paranoid SZ was much more similar to non-paranoid SZ than DD. Relative to subjects with SZ, those with DD were more likely to have drug abuse before illness onset, better premorbid sexual adjustment, later age at illness onset, higher levels of affective symptoms and lack of insight, poorer response to antipsychotic medication, better functioning in the domains of personal care, paid work and social functioning; last, subjects with DD had fewer but more severe delusions and higher ratings of conviction of delusional experience than those with SZ. Predominance of jealousy and somatic delusions was confined to subjects with DD. CONCLUSIONS: DD and SZ represent two distinct classes of disorders, the differential features of DD being of nosological, aetiological and therapeutic relevance.

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En adultos, se ha demostrado que la metformina favorece la reducción de peso y previene el desarrollo de Diabetes Mellitus tipo 2 (DM2). Sin embargo, aún no se han determinado estos efectos en población adolescente con riesgo de DM2. Objetivo: Analizar el impacto antropométrico y metabólico de la metformina en adolescentes obesas con riesgo de DM2. Pacientes y Método: Estudio randomizado, doble ciego, en que participaron 19 adolescentes obesas con riesgo de DM2 distribuidas aleatoriamente en dos grupos. Ambos fueron sometidos a un período de tratamiento (3 meses) con cambios en estilo de vida y farmacoterapia (dosis diaria de metformina 500 mg de liberación prolongada o placebo, respectivamente), continuado por un período de seguimiento (3 meses). Se compararon las variaciones en antropometría (peso, IMC, circunferencia cintura, presión arterial) y perfil metabólico (glicemia, HOMA, perfil lipídico, GOT y GPT) entre ellos al finalizar ambos períodos. Resultados: El grupo tratado con metformina mostró reducción significativa del peso e IMC. La disminución de IMC fue significativamente mayor que la del grupo que recibió placebo. Ningún grupo demostró mejora en el perfil de riesgo metabólico. Conclusión: La terapia con metformina, combinada con intervención en el estilo de vida, reduce el peso e IMC en adolescentes obesas con riesgo de DM2 en comparación con pacientes que reciben intervención en estilo de vida y placebo.

In adults, metformin promotes weight loss and prevents the development of type 2 diabetes mellitus (DM2). However, these effects have not been demonstrated in adolescents at risk for DM2. Objective: To analyze the anthropometric and metabolic impact of metformin in obese adolescents at risk for DM2. Patients and Methods: A double-blind, placebo-controlled study was conducted in 19 obese female adolescents at risk for DM2. A structured lifestyle intervention with nutritional and exercise education and motivational support was assessed over 3 month with an additional follow up period of 3 months. Subjects were randomized to 500 mg/ daily of extended release metformin or placebo. Anthropometric (weight, BMI, waist circumference, blood pressure) and metabolic profiles (glycemia, HOMA, lipid profile, AST, ALT) were compared between both groups at the end of both periods. Results: Metformin treated group showed a significant reduction in weight and body mass index (BMI) compared with placebo group. No improvement in the metabolic risk profile was showed in any group. Conclusion: In this study, metformin therapy in combination with a lifestyle intervention helps to reduce weight and BMI in obese adolescent females at risk for DM2, compared to lifestyle and placebo intervention.

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PURPOSE: To test whether the association between childhood adversity and positive and negative psychotic experiences is due to genetic confounding. METHOD: Childhood adversity and psychotic experiences were assessed in an ongoing sample of 226 twins from the general population. A monozygotic (MZ) twin differences approach was used to assess possible genetic confounding. RESULTS: In the whole sample, childhood adversity was significantly associated with positive (ß=45; SE=0.16; P=0.008) and negative psychotic experiences (ß=0.77; SE=0.18; P<0.01). Within-pair MZ twin differences in exposure to childhood adversity were significantly associated with differences in positive (ß=71; SE=0.29; P=0.016) and negative psychotic experiences (ß=98; SE=0.38; P=0.014) in a subsample of 85 MZ twin pairs. CONCLUSIONS: Individuals exposed to childhood adversity are more likely to report psychotic experiences. Furthermore, our findings indicate that this association is not due to genetic confounding.

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In adults, metformin promotes weight loss and prevents the development of type 2 diabetes mellitus (DM2). However, these effects have not been demonstrated in adolescents at risk for DM2. Objective: To analyze the anthropometric and metabolic impact of metformin in obese adolescents at risk for DM2. Patients and Methods: A double-blind, placebo-controlled study was conducted in 19 obese female adolescents at risk for DM2. A structured lifestyle intervention with nutritional and exercise education and motivational support was assessed over 3 month with an additional follow up period of 3 months. Subjects were randomized to 500 mg/ daily of extended release metformin or placebo. Anthropometric (weight, BMI, waist circumference, blood pressure) and metabolic profiles (glycemia, HOMA, lipid profile, AST, ALT) were compared between both groups at the end of both periods. Results: Metformin treated group showed a significant reduction in weight and body mass index (BMI) compared with placebo group. No improvement in the metabolic risk profile was showed in any group. Conclusion: In this study, metformin therapy in combination with a lifestyle intervention helps to reduce weight and BMI in obese adolescent females at risk for DM2, compared to lifestyle and placebo intervention.

En adultos, se ha demostrado que la metformina favorece la reducción de peso y previene el desarrollo de Diabetes Mellitus tipo 2 (DM2). Sin embargo, aún no se han determinado estos efectos en población adolescente con riesgo de DM2. Objetivo: Analizar el impacto antropométrico y metabólico de la metformina en adolescentes obesas con riesgo de DM2. Pacientes y Método: Estudio randomizado, doble ciego, en que participaron 19 adolescentes obesas con riesgo de DM2 distribuidas aleatoriamente en dos grupos. Ambos fueron sometidos a un período de tratamiento (3 meses) con cambios en estilo de vida y farmacoterapia (dosis diaria de metformina 500 mg de liberación prolongada o placebo, respectivamente), continuado por un período de seguimiento (3 meses). Se compararon las variaciones en antropometría (peso, IMC, circunferencia cintura, presión arterial) y perfil metabólico (glicemia, HOMA, perfil lipídico, GOT y GPT) entre ellos al finalizar ambos períodos. Resultados: El grupo tratado con metformina mostró reducción significativa del peso e IMC. La disminución de IMC fue significativamente mayor que la del grupo que recibió placebo. Ningún grupo demostró mejora en el perfil de riesgo metabólico. Conclusión: La terapia con metformina, combinada con intervención en el estilo de vida, reduce el peso e IMC en adolescentes obesas con riesgo de DM2 en comparación con pacientes que reciben intervención en estilo de vida y placebo.

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BACKGROUND: There is a lack of consistent evidence regarding associations of neurological soft signs (NSS) with illness-related variables in schizophrenia. This study examined NSS in first-episode psychotic patients with respect to their factor structure and associations with risk factors, pre-morbid characteristics, psychopathology and spontaneous extrapyramidal syndromes. METHOD: First-episode, drug-naive patients with schizophrenia-spectrum disorders (n=177) were assessed for NSS using the Neurological Evaluation Scale, and its 26 constituting items were factor analysed. The identified neurological dimensions were then entered into hierarchical regression models as outcome dependent variables of a set of predictors including risk factors (familial loading for schizophrenia, obstetric complications), pre-morbid characteristics (neurodevelopmental delay, symptoms of attention deficit-hyperactivity disorder, pre-morbid functioning), psychopathological domains (reality distortion, disorganization, negative symptoms, mania, depression, catatonia) and spontaneous extrapyramidal syndromes (parkinsonism, dyskinesia, akathisia). RESULTS: Five neurological domains were identified: sequencing, release signs, sensory integration, abnormal movements and coordination. Multivariate analyses showed independent associations (p<0.01) of sequencing with familial liability to schizophrenia, deterioration of pre-morbid adjustment and parkinsonism; release signs with obstetric complications, catatonic symptoms and parkinsonism; sensory integration with familial liability to schizophrenia; abnormal movements with familial liability to schizophrenia, obstetric complications, parkinsonism and dyskinesia; and coordination with neurodevelopmental delay. The empirically derived factors explained additional variance over and above that explained by subscale scores across the examined variables. CONCLUSIONS: Familial liability to schizophrenia, obstetric complications, neurodevelopmental delay, deterioration in pre-morbid functioning and observable motor disorders appear to contribute independently to domains of neurological dysfunction. The findings support a neurodevelopmental model of NSS in schizophrenia.

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