High blood levels of brain-derived neurotrophic factor (BDNF) mRNA in early psychosis are associated with inflammatory markers.

The brain-derived neurotrophic factor (BDNF) single nucleotide polymorphism (SNP) rs6265C > T, Val66Met, affects BDNF secretion and has been related to inflammatory processes. Both the rs6265 and BDNF protein levels have been widely investigated in neuropsychiatric disorders with conflicting results. In the present study we examined BDNF mRNA expression in blood considering the SNP rs6265 and its relationship with inflammatory markers in the early stages of psychosis. The rs6265 genotype and blood BDNF mRNA levels were measured in 34 at-risk mental states (ARMS) individuals, 37 patients with first-episode psychosis (FEP) and 42 healthy controls (HCs) by quantitative PCR and reverse transcription (RT)-qPCR using validated TaqMan assays. We also obtained measures of interleukin-6 (IL6) mRNA levels, fibrinogen, neutrophil-to-lymphocyte ratio (NLR) and high-sensitivity C-reactive protein. We identified that BDNF mRNA levels were associated with the rs6265 genotype in an allele-dose-dependent manner, with low expression levels associated with the T allele (Met substitution). Thus, we controlled for the rs6265 genotype in all analyses. Blood BDNF mRNA levels differed between diagnostic groups: patients with FEP exhibited higher blood BDNF mRNA levels than ARMS individuals, and the lowest levels were observed in HC. In addition, we observed significant correlations between BDNF mRNA levels and inflammatory markers (IL6 mRNA levels and NLR), controlled by the rs6265 genotype, in ARMS and FEP groups. This exploratory study suggests that the rs6265 genotype is associated with differential blood mRNA expression of BDNF that increases with illness progression and correlated with inflammation in the early stages of psychosis.

Risk factors for metabolic syndrome in individuals with recent-onset psychosis at disease onset and after 1-year follow-up.

Metabolic syndrome (MetS) is a cluster of parameters encompassing the most dangerous heart attack risk factors, associated with increased morbidity and mortality. It is highly prevalent in recent-onset psychosis (ROP) patients. In this pilot study, we evaluated MetS parameters (fasting glucose, high-density lipoprotein (HDL) cholesterol (HDL-c), fasting triglycerides, waist circumference, and systolic and diastolic blood pressure), clinical symptoms, pharmacological treatment, lifestyle, and inflammatory markers in 69 patients with ROP and 61 healthy controls (HCs). At baseline, waist circumference (p = 0.005) and fasting triglycerides (p = 0.007) were higher in patients with ROP than in HCs. At the 1-year follow-up, patients showed clinical improvement, with a reduction in the positive and negative syndrome scale (PANSS) score (p < 0.001), dietary intake (p = 0.001), and antipsychotic medication dose (p < 0.001); however, fasting glucose (p = 0.011), HDL-c (p = 0.013) and waist circumference worsened (p < 0.001). We identified sex, age, BMI, dietary intake, physical activity, daily tobacco use, daily cannabis use, and antipsychotic doses as risk factors contributing to baseline MetS parameters. After 1-year follow-up, those factors plus the PANSS and Calgary Depression Scale for Schizophrenia (CDSS) scores were associated with MetS parameters. Further studies are needed to understand the contributions of the studied risk factors in patients with ROP at onset and during disease progression.

A polygenic approach to the association between smoking and schizophrenia.

Smoking prevalence in schizophrenia is considerably larger than in general population, playing an important role in early mortality. We compared the polygenic contribution to smoking in schizophrenic patients and controls to assess if genetic factors may explain the different prevalence. Polygenic risk scores (PRSs) for smoking initiation and four genetically correlated traits were calculated in 1108 schizophrenic patients (64.4% smokers) and 1584 controls (31.1% smokers). PRSs for smoking initiation, educational attainment, body mass index and age at first birth were associated with smoking in patients and controls, explaining a similar percentage of variance in both groups. Attention-deficit hyperactivity disorder (ADHD) PRS was associated with smoking only in schizophrenia. This association remained significant after adjustment by psychiatric cross-disorder PRS. A PRS combining all the traits was more explanative than smoking initiation PRS alone, indicating that genetic susceptibility to the other traits plays an additional role in smoking behaviour. Smoking initiation PRS was also associated with schizophrenia in the whole sample, but the significance was lost after adjustment for smoking status. This same pattern was observed in the analysis of specific SNPs at the CHRNA5-CHRNA3-CHRNB4 cluster associated with both traits. Overall, the results indicate that the same genetic factors are involved in smoking susceptibility in schizophrenia and in general population and are compatible with smoking acting, directly or indirectly, as a risk factor for schizophrenia that contributes to the high prevalence of smoking in these patients. The contrasting results for ADHD PRS may be related to higher ADHD symptomatology in schizophrenic patients.

The shared genetic architecture of schizophrenia, bipolar disorder and lifespan.

Psychiatric disorders such as Schizophrenia (SCZ) and Bipolar Disorder (BD) represent an evolutionary paradox, as they exhibit strong negative effects on fitness, such as decreased fecundity and early mortality, yet they persist at a worldwide prevalence of approximately 1%. Molecular mechanisms affecting lifespan, which may be widely common among complex diseases with fitness effects, can be studied by the integrated analysis of data from genome-wide association studies (GWAS) of human longevity together with any disease of interest. Here, we report the first of such studies, focusing on the genetic overlap-pleiotropy-between two psychiatric disorders with shortened lifespan, SCZ and BD, and human parental lifespan (PLS) as a surrogate of life expectancy. Our results are twofold: first, we demonstrate extensive polygenic overlap between SCZ and PLS and to a lesser extent between BD and PLS. Second, we identified novel loci shared between PLS and SCZ (n = 39), and BD (n = 8). Whereas most of the identified SCZ (66%) and BD (62%) pleiotropic risk alleles were associated with reduced lifespan, we also detected some antagonistic protective alleles associated to shorter lifespans. In fact, top-associated SNPs with SCZ seems to explain longevity variance explained (LVE) better than many other life-threatening diseases, including Type 2 diabetes and most cancers, probably due to a high overlap with smoking-related pathways. Overall, our study provides evidence of a genetic burden driven through premature mortality among people with SCZ, which can have profound implications for understanding, and potentially treating, the mortality gap associated with this psychiatric disorder.

Glycated Haemoglobin Is Associated With Poorer Cognitive Performance in Patients With Recent-Onset Psychosis.

BACKGROUND: Glucose abnormalities and cognitive alterations are present before the onset of schizophrenia. We aimed to study whether glucose metabolism parameters are associated with cognitive functioning in recent-onset psychosis (ROP) patients while adjusting for hypothalamic-pituitary adrenal (HPA) axis measures. METHODS: Sixty ROP outpatients and 50 healthy subjects (HS) were studied. Cognitive function was assessed with the MATRICS Consensus Cognitive Battery. Glycated haemoglobin (HbA1c), glucose, insulin, and C-peptide levels were determined in plasma. The HOMA-insulin resistance index was calculated. Salivary samples were obtained at home on another day to assess the cortisol awakening response and cortisol levels during the day. Univariate analyses were conducted to explore the association between glucose metabolism parameters and cognitive tasks. For those parameters that were more clearly associated with the cognitive outcome, multiple linear regression analyses were conducted to adjust for covariates. Each cognitive task was considered the dependent variable. Covariates were age, sex, education level, diagnosis, antipsychotic and benzodiazepine treatment, body mass index (BMI), smoking, and HPA axis measures. Potential interactions between diagnosis and glucose parameters were tested. RESULTS: There were no significant differences in HPA axis measures or glucose parameters, with the exception of C-peptide (that was higher in ROP patients), between groups. ROP patients had a lower performance than HS in all cognitive tasks (p < 0.01 for all tasks). Of all glucose metabolism parameters, HbA1c levels were more clearly associated with cognitive impairment in cognitive tasks dealing with executive functions and visual memory in both ROP patients and HS. Multivariate analyses found a significant negative association between HbA1c and cognitive functioning in five cognitive tasks dealing with executive functions, visual memory and attention/vigilance (a ROP diagnosis by HbA1c negative interaction was found in this latter cognitive domain, suggesting that HBA1c levels are associated with impaired attention only in ROP patients). CONCLUSIONS: Our study found that HbA1c was negatively associated with cognitive functioning in both ROP patients and HS in tasks dealing with executive functions and visual memory. In ROP patients, HbA1c was also associated with impaired attention. These results were independent of BMI and measures of HPA axis activity.

Clinical and cognitive correlates of childhood attention-deficit/hyperactivity disorder in first-episode psychosis: A controlled study.

The relationship between childhood attention-deficit/hyperactivity disorder (c-ADHD) and psychosis has been understudied. Cognitive dysfunction is a core feature of both disorders, but no previous study has investigated whether first-episode psychosis (FEP) with c-ADHD (FEP-ADHD+) presents a different cognitive profile than FEP without c-ADHD (FEP-ADHD-). One hundred and thirty-three FEP outpatients were screened for c-ADHD through a diagnostic interview and underwent a comprehensive clinical and cognitive assessment with the MATRICS Consensus Cognitive Battery (MCCB). Cognitive differences among FEP groups, and a group of 65 healthy controls (HCs) were analysed by multivariate analysis of covariance. Nearly 25% of FEP fulfilled criteria for c-ADHD. Both FEP groups performed worse than HCs in speed processing, executive function and social cognition, but only the FEP-ADHD+group was significantly more impaired than the HC group in attention (F = 4.35; p = 0.04). Only the Trail Making Test A (TMT-A) (F = 6.99; p = 0.01) within the domain of processing speed and the Neuropsychological Assessment Battery (NAB) (F = 6.46; p = 0.01) within the domain of executive function reliably differentiated the two clinical groups. The FEP groups did not differ in the severity of psychopathology, but the FEP-ADHD+reported fewer years of education than the FEP-ADHD- and were more likely to use tobacco and cannabis and to require higher doses of antipsychotics to achieve a clinical response. In conclusion, we found a gradient of severity in cognitive performance between groups, with FEP-ADHD+ having the greatest cognitive impairment. Our results suggest that FEP-ADHD+ represents a subgroup with a worse prognosis than FEP-ADHD-.

Hypothalamic-pituitary-adrenal axis function and exposure to stress factors and cannabis use in recent-onset psychosis.

Objectives: Previous studies suggest that childhood trauma, stressful life events, and cannabis use are associated with psychosis. We aimed to explore whether these environmental factors have an effect on hypothalamic-pituitary-adrenal (HPA) axis indices in recent-onset psychosis.Methods: We studied 56 recent-onset psychosis outpatients and 47 healthy controls. Childhood trauma was assessed with the Childhood Trauma Questionnaire. Stressful life events were assessed with the Holmes-Rahe Social Readjustment Scale. Cannabis use was assessed by semistructured interviews. Several HPA axis measures were analysed in saliva: cortisol awakening response (CAR), diurnal cortisol slope, and dexamethasone suppression test ratio (DSTR) after 0.25 mg of dexamethasone. Multiple linear regression analyses were conducted to explore the contribution of environmental factors to each HPA axis measure while adjusting for covariates (diagnosis, age, gender, smoking, body mass index and treatments).Results: There were no significant differences in HPA axis measures between diagnostic groups. Cannabis use was associated with a more flattened diurnal cortisol slope (standardized ß = 0.21, p = 0.038), independent of recent-onset psychosis diagnosis. No associations were found between environmental factors and other HPA axis measures (CAR, DSTR).Conclusions: Our study provides evidence for the effect of cannabis exposure in cortisol secretion patterns in both healthy controls and recent-onset psychosis patients.

Expression of DDR1 in the CNS and in myelinating oligodendrocytes.

Discoidin domain receptor 1 (DDR1) is a tyrosine kinase receptor that is activated by fibrillar collagens. Here, we review the expression and role of DDR1 in the central nervous system (CNS). In a murine model, DDR1 is expressed in oligodendrocytes in the developing brain and during remyelination. In human adult brain tissue, DDR1 is detected in a similar pattern as other classical myelin proteins such as myelin basic protein (MBP). Up to 50 transcripts of DDR1 have been detected in human tissues, of which 5 isoforms have been identified. In the human brain, all 5 isoforms are detectable, but DDR1b is the most highly expressed, and DDR1c is coexpressed with myelin genes. DDR1 sequence variants have been associated with psychiatric disorders, and upregulation of this gene occurs in gliomas. Moreover, mutations in DDR1 have been found in tumors of Schwann cells, which are the myelinating cells of the peripheral nervous system. All these data suggest that DDR1 plays a role in myelination and is relevant to neuropsychiatric diseases.

Increased levels of serum leptin in the early stages of psychosis.

BACKGROUND: Studies evaluating leptin levels in patients with first-episode psychoses (FEP) have been inconclusive, and apparently, the high levels of leptin reported in patients with schizophrenia may be associated with weight gain. The aim of this study was to evaluate leptin levels at the early stages of the disease and the relationship between leptin and lifestyle habits, stress-related variables and metabolic parameters. METHODS: In total, 14 at-risk mental state (ARMS) patients, 39 FEP patients, 32 psychotic patients in the critical period (CP) and 21 healthy controls (HCs) were assessed. Anthropometric and biochemical parameters, as well as dietary intake, physical activity, stress-related variables and symptomatology, were collected. RESULTS: Leptin levels were higher in the ARMS, FEP and CP patients than in the HCs. After controlling for age, sex, BMI, physical exercise, tobacco use and dietary intake, the highest differences in leptin levels were observed between the ARMS patients and HCs (p = 0.025). In the whole sample, leptin levels were positively correlated with BMI (p < 0.001), waist circumference (p < 0.001), insulin levels (p = 0.020), levels of the inflammatory marker IL-6 (p = 0.007) and energy intake (p = 0.043) and negatively correlated with HDL cholesterol (p = 0.018). Interestingly, energy intake and food craving scores were positively correlated with levels of leptin only in females (p = 0.022 and p = 0.036, respectively). DISCUSSION: The present study detected increased leptin levels in the early stages of psychosis and significant correlations between leptin levels and anthropometric, lipid, hormone, and cytokine parameters. We found higher leptin levels in women, and we identified dietary intake habits associated with leptin exclusively in females that advocate considering sex in future studies.

Mitochondrial dysfunction in a family with psychosis and chronic fatigue syndrome.

Mitochondrial impairment is hypothesized to be involved in chronic fatigue syndrome (CFS) and schizophrenia. We performed a clinical, genetic and functional mitochondrial study in a family consisting of a female presenting schizophrenia in addition to CFS symptoms and her mother and older sister, both presenting with CFS. The three family members showed higher blood lactate levels, higher mitochondrial mass, lower mtDNA content and overall lower mitochondrial enzymatic activities and lower oxygen consumption capacities than healthy women. This family presented mtDNA depletion; however, no mutation was identified neither in the mtDNA nor in the nuclear genes related with mtDNA depletion, even though C16179A and T16519A variants should be further studied.

In silico, in vitro and case-control analyses as an effective combination for analyzing BRCA1 and BRCA2 unclassified variants in a population-based sample.

Ascertaining the clinical consequences of BRCA1 and BRCA2 variants of uncertain significance (VUS) is currently indispensable for providing effective genetic counseling and preventive actions for families with hereditary breast and ovarian cancer (HBOC). To this end, we conducted a combination of in silico prediction and cDNA splicing analyses of 13 BRCA1 and 10 BRCA2 VUS identified in our cohort as well as a case-control analysis in a population-based sample of 10 recurrent VUS. We observed consistent results between the in silico predictions and sequencing analyses for all analyzed VUS. An abnormal cDNA pattern was observed for variants c.212+1G>A and c.5278-1G>A in BRCA1 and c.516+2T>A and c.8168A>G in BRCA2 according to in silico splicing prediction. A case-control study of VUS confirmed the polymorphisms of the c.67+62A>G, c.7008-62A>G and c.8851G>A BRCA2 variants previously published. c.4068G>A in the BRCA2 gene can also be considered a polymorphism due to its occurrence at a frequency greater than 1% in our population. Our study shows that employing population-based analysis and a combination of several in silico methods yields highly accurate information, resulting in a reliable tool for selecting variants for cDNA sequencing analysis in routine cancer genetic counseling units.

Pharmacogenetic study of the effects of raloxifene on negative symptoms of postmenopausal women with schizophrenia: A double-blind, randomized, placebo-controlled trial.

Several double-blind clinical trials have reported improvement in positive, negative and cognitive symptoms of schizophrenia with raloxifene, a selective receptor estrogen modulator. However, there are some inconsistencies in replicating findings between studies of different countries. The failure to replicate these findings may result from genetic factors that could explain some of the variability in the treatment response. However, pharmacogenetic studies exploring this topic in women with schizophrenia are lacking. We aimed to conduct an exploratory pharmacogenetic analysis of a double-blind, randomized, parallel, placebo-controlled study of 24 weeks' duration of raloxifene aiming to improve negative symptoms in postmenopausal women with schizophrenia. Four single nucleotide polymorphisms (SNPs) were studied: rs9340799, rs2234693 and rs1801132 in the Estrogen Receptor 1 (ESR1) gene, and rs1042597 in the UDP-glucuronosyltransferase 1A8 (UGT1A8) gene. Sixty-five postmenopausal women with schizophrenia (DSM-IV) were randomized to either 60mg/day adjunctive raloxifene (36 women) or adjunctive placebo (29 women). Psychopathological symptoms were assessed at baseline and at weeks 4, 12, and 24 with the Positive and Negative Syndrome Scale (PANSS). Of the four studied SNPs, the rs1042597 variant in the UGT1A8 gene was associated with a different treatment response in negative symptoms with raloxifene treatment, whereas the rs2234693 variant in the ESR1 gene was associated with a distinct response in general psychopathology. In conclusion, our study suggests that genetic variants in UGT1A8 and ESR1 genes modulate the treatment response to adding raloxifene to antipsychotic treatment in postmenopausal women with schizophrenia.

Hypothalamic-pituitary-adrenal axis measures and cognitive abilities in early psychosis: Are there sex differences?

INTRODUCTION: Measures of hypothalamic-pituitary-adrenal (HPA) axis activity such as increased diurnal cortisol levels or a blunted cortisol awakening response (CAR) have been associated with cognitive impairments in people with psychotic disorders. We aimed to explore whether there are sex differences in the relationship between HPA axis measures and cognition in early psychosis (EP). METHODS: 60 EP outpatients and 50 healthy subjects (HS) were assessed with the MATRICS Consensus Cognitive Battery. Saliva cortisol levels were determined at the neuropsychological assessment and on another day at 6 sampling times: awakening; 30' and 60' post-awakening; and 10:00h, 23:00h and 10:00h the day after the administration of 0.25mg of dexamethasone, which occurred at 23:00h. Three HPA axis measures were calculated: CAR, cortisol diurnal slope and cortisol suppression ratio of the dexamethasone suppression test (DST). Multiple linear regression analyses were conducted to explore the relationship between HPA axis measures and cognitive tasks while adjusting for covariates (education level, smoking, cannabis use, and cortisol levels at the cognitive assessment). Interactions between female sex, EP diagnosis and HPA axis measures were examined. RESULTS: An increased CAR was associated with a poorer cognitive performance in EP women in processing speed and verbal memory. In contrast, a more flattened diurnal cortisol slope was associated with poorer functioning in the spatial working memory of EP women. DST suppression ratio was associated with better visual memory, without sex differences. CONCLUSIONS: Our study suggests that there are sex differences in the relationship between HPA axis measures and cognitive abilities in EP.

Coping strategies for postpartum depression: a multi-centric study of 1626 women.

The transition to motherhood is stressful as it requires several important changes in family dynamics, finances, and working life, along with physical and psychological adjustments. This study aimed at determining whether some forms of coping might predict postpartum depressive symptomatology. A total of 1626 pregnant women participated in a multi-centric longitudinal study. Different evaluations were performed 8 and 32 weeks after delivery. Depression was assessed using the Edinburgh Postnatal Depression Scale (EPDS) and the structured Diagnostic Interview for Genetic Studies (DIGS). The brief Coping Orientation for Problem Experiences (COPE) scale was used to measure coping strategies 2-3 days postpartum. Some coping strategies differentiate between women with and without postpartum depression. A logistic regression analysis was used to explore the relationships between the predictors of coping strategies and major depression (according to DSM-IV criteria). In this model, the predictor variables during the first 32 weeks were self-distraction (OR 1.18, 95 % CI 1.04-1.33), substance use (OR 0.58, 95 % CI 0.35-0.97), and self-blame (OR 1.18, 95 % CI 1.04-1.34). In healthy women with no psychiatric history, some passive coping strategies, both cognitive and behavioral, are predictors of depressive symptoms and postpartum depression and help differentiate between patients with and without depression.

A Non-Interventional Naturalistic Study of the Prescription Patterns of Antipsychotics in Patients with Schizophrenia from the Spanish Province of Tarragona.

BACKGROUND: The analysis of prescribing patterns in entire catchment areas contributes to global mapping of the use of antipsychotics and may improve treatment outcomes. OBJECTIVE: To determine the pattern of long-term antipsychotic prescription in outpatients with schizophrenia in the province of Tarragona (Catalonia-Spain). METHODS: A naturalistic, observational, retrospective, non-interventional study based on the analysis of registries of computerized medical records from an anonymized database of 1,765 patients with schizophrenia treated between 2011 and 2013. RESULTS: The most used antipsychotic was risperidone, identified in 463 (26.3%) patients, followed by olanzapine in 249 (14.1%), paliperidone in 225 (12.7%), zuclopenthixol in 201 (11.4%), quetiapine in 141 (8%), aripiprazole in 100 (5.7%), and clozapine in 100 (5.7%). Almost 8 out of 10 patients (79.3%) were treated with atypical or second-generation antipsychotics. Long-acting injectable (LAI) formulations were used in 44.8% of patients. Antipsychotics were generally prescribed in their recommended doses, with clozapine, ziprasidone, LAI paliperidone, and LAI risperidone being prescribed at the higher end of their therapeutic ranges. Almost 7 out of 10 patients (69.6%) were on antipsychotic polypharmacy, and 81.4% were on psychiatric medications aside from antipsychotics. Being prescribed quetiapine (OR 14.24, 95% CI 4.94-40.97), LAI (OR 9.99, 95% CI 6.45-15.45), psychiatric co-medications (OR 4.25, 95% CI 2.72-6.64), and paliperidone (OR 3.13, 95% CI 1.23-7.92) were all associated with an increased likelihood of polypharmacy. Being prescribed risperidone (OR 0.54, 95% CI 0.35-0.83) and older age (OR 0.98, 95% CI 0.97-0.99) were related to a low polypharmacy probability. CONCLUSIONS: Polypharmacy is the most common pattern of antipsychotic use in this region of Spain. Use of atypical antipsychotics is extensive. Most patients receive psychiatric co-medications such as anxiolytics or antidepressants. Polypharmacy is associated with the use of quetiapine or paliperidone, use of a LAI, younger age, and psychiatric co-medication.

Increased serum interleukin-6 levels in early stages of psychosis: associations with at-risk mental states and the severity of psychotic symptoms.

Schizophrenia patients experience activated inflammatory responses, but little is known about the presence of such inflammatory processes at or prior to disease onset. We measured interleukin-6 (IL-6) and C-reactive protein (CRP) serum levels and plasma fibrinogen in 17 at-risk mental state (ARMS) subjects, 77 patients with psychotic disorder (PD) and 25 healthy control subjects (HC). ARMS subjects were followed-up, and transition to psychosis was registered. IL6 rs1800795 SNP was genotyped, as IL-6 levels may be influenced by this genetic variant. We did not observe significant differences in the IL6 rs1800795 SNP genotype frequencies between the groups. ARMS subjects exhibited significantly higher IL-6 levels than did controls (p=0.019). In subjects not taking cannabis, we found that patients diagnosed with ARMS or PD exhibited increased IL-6 levels when compared with HC (p=0.004). In both ARMS and PD subjects, IL-6 levels were positively associated with negative symptoms. However, with respect to positive psychotic symptoms, a different relationship was observed in the ARMS and PD groups (positive relationship in ARMS; negative relationship in PD). These findings could not be attributed to confounding variables, including gender, body mass index (BMI), tobacco consumption or the rs1800795 genotype. Six of 17 ARMS subjects (35%) exhibited a transition to psychosis during the follow-up period of 26 months. ARMS subjects who developed psychosis exhibited increased median IL-6 levels compared with those who did not transition (0.61 vs. 0.35pg/mL). However, this difference was not statistically significant, which could be explained by a lack of statistical power due to the small sample size. Our results suggest that IL-6 may be a biomarker for early psychotic symptoms; however, further studies in larger samples are needed to confirm this result.

Unhealthy lifestyle in early psychoses: the role of life stress and the hypothalamic-pituitary-adrenal axis.

An unhealthy lifestyle is thought to contribute to the metabolic syndrome in subjects with psychoses. In the present study we aimed to study whether life stress or cortisol measures may influence dietary patterns in subjects with early stages of psychoses. We studied 81 subjects with early psychoses (65 subjects with a psychotic disorder [PD] and <5 years of illness; 16 subjects at risk for psychosis [high-risk, HR]) and a control group of 25 healthy subjects (HS). Dietary habits were examined by a dietician, who registered food intake (24h recall). Physical activity was assessed by validated questionnaire. Life stress was assessed with Holmes-Rahe Social Readjustment Scale. Fasting morning salivary and plasma cortisol levels were determined. We found that PD and HR reported an unhealthier lifestyle with more smoking, reduced physical activity and poorer dietary habits. HR reported increased intake of calories and saturated fatty acids and reduced protein consumption, when compared to HS. Life stress was a predictor of these adverse behaviours, although we found opposite associations in HR and PD. Life stress was associated with increased intake of refined sugar in PD and decreased intake in HR and HS. Salivary cortisol was related to increased intake of saturated fat only in HR subjects, but cortisol levels in plasma or saliva were not associated with other dietary habits or obesity measures (BMI, waist circumference). Our study suggests that unhealthy diet in early psychoses is influenced by stress, but our data do not support this effect being mediated by hypercortisolism. Future preventive interventions in psychosis may target dietary habits, particularly for those who are at risk for psychosis.

Differential association of circadian genes with mood disorders: CRY1 and NPAS2 are associated with unipolar major depression and CLOCK and VIP with bipolar disorder.

Disruptions in circadian rhythms have been described in mood disorders (MD), but the involvement of genetic variation in genes pertaining to the molecular circadian machinery in the susceptibility to MD has not been conclusively determined. We examined 209 single-nucleotide polymorphisms (SNPs) covering 19 circadian genes (ADCYAP1, ARNTL, ARNTL2, BHLHB2, BHLHB3, CLOCK, CRY1, CRY2, CSNK1E, DBP, NPAS2, NR1D1, PER1, PER2, PER3, RORA, TIMELESS, VIP, and VIPR2) in a sample of 534 MD patients (335 with unipolar major mood depression (MDD) and 199 with bipolar disorder (BD)) and 440 community-based screened controls. Nominally, statistically significant associations were found in 15 circadian genes. The gene-wide test, corrected for the number of SNPs analyzed in each gene, identified significant associations in CRY1 (rs2287161), NPAS2 (rs11123857), and VIPR2 (rs885861) genes with the combined MD sample. In the MDD subsample, the same SNPs in CRY1 and NPAS2 of the combined sample remained associated, whereas in the BD subsample CLOCK (rs10462028) and VIP (rs17083008) were specifically associated. The association with an SNP located 3' near CRY1 gene in MDD remained statistically significant after permutation correction at experiment level (p=0.007). Significant additive effects were found between the SNPs that were statistically significant at the gene-wide level. We also found evidence of associations between two-marker haplotypes in CRY1 and NPAS2 genes and MD. Our data support the contribution of the circadian system to the genetic susceptibility to MD and suggest that different circadian genes may have specific effects on MD polarity.

A free radical-generating system induces the cholesterol biosynthesis pathway: a role in Alzheimer's disease.

Oxidative stress, which plays a critical role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), is intimately linked to aging - the best established risk factor for AD. Studies in neuronal cells subjected to oxidative stress, mimicking the situation in AD brains, are therefore of great interest. This paper reports that, in human neuronal cells, oxidative stress induced by the free radical-generating xanthine/xanthine oxidase (X-XOD) system leads to apoptotic cell death. Microarray analyses showed a potent activation of the cholesterol biosynthesis pathway following reductions in the cell cholesterol synthesis caused by the X-XOD treatment; furthermore, the apoptosis was reduced by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) expression with an interfering RNA. The potential importance of this mechanism in AD was investigated by genetic association, and it was found that HMGCR, a key gene in cholesterol metabolism and among those most strongly upregulated, was associated with AD risk. In summary, this work presents a human cell model prepared to mimic the effect of oxidative stress in neurons that might be useful in clarifying the mechanism involved in free radical-induced neurodegeneration. Gene expression analysis followed by genetic association studies indicates a possible link among oxidative stress, cholesterol metabolism and AD.