Studies suggest that prenatal use of folic acid (FA) or iron may reduce risk of autism spectrum disorders (ASD). These findings require verification.

To examine prenatal use of FA, iron, and multivitamins and risk of ASD with and without intellectual disability (ID).

Data on 254,405 mother/child pairs born 1996-2007 (1,074 ASD with ID; 3,700 ASD without ID) were drawn from the Stockholm Youth Cohort, a register-based cohort in Stockholm County, Sweden. Supplement use was assessed at first antenatal visit. The sample was categorized as: users of multivitamin or multiple supplements (N=43,634); FA use only (8,494); iron use only (53,575); and non-use (148,702). Covariates included maternal (age, obesity, national origin, family income, medications, medical and psychiatric history) and child factors (sex, birthyear).

Supplement users were different from non-users across multiple medical and social characteristics. In adjusted models, compared to risk of ASD with ID in non-users, odds ratios (95% CI) were: multivitamin use: 0.79 (0.65-0.95); iron use: 1.10 (0.95, 1.27); FA use: 1.40 (1.04, 1.88). Supplement use was not associated with ASD without ID.

The apparent increased risk of ASD with ID for FA may be because FA is prescribed for women with neurological disorders that increase risk of child ASD. Although results suggest multivitamin use is associated with lower risk of ASD with ID, confounding is likely since users were very different from non-users. Even if associations were causal, whether a particular nutrient is protective cannot be identified since formulations include multiple nutrients.

There is a lack of objective methods for continuous monitoring of illness activity in bipolar disorder. Smartphones offer novel and unique opportunities for monitoring of symptoms and collection of real-time data.

To test the hypothesis that automatically generated objective data and self-monitored correlate with clinically rated depressive and manic symptoms in patients with bipolar disorder.

Software for smartphones (the MONARCA system) was developed by our group. This system allows for continuous collection of automatically generated objective data and self-monitored data. A total of 61 patients with bipolar disorder aged 18-60 years used the MONARCA system for a six months period. Patients were rated, by a researcher blinded to smartphone data, once a month for six months using Hamilton Depression Rating Scale 17-item (HDRS-17) and Young Mania Rating Scale (YMRS).

Data showed significant correlations between automatically generated objective data (the number of incoming and outgoing phone calls/ day, the duration of incoming and outgoing phone calls/ day, and the number of outgoing text messages/ day) and depressive and manic symptoms according to HDRS-17 and YMRS, respectively. Data showed significant correlations between self-monitored data (mood, sleep, activity level and stress level) and depressive and manic symptoms according to HDRS-17 and YMRS, respectively.

Automatically generated objective data and self-monitored data collected using the MONARCA system correlate with clinically rated depressive and manic symptoms in patients with bipolar disorder. Smartphone apps reflect an easy and objective way to continuously monitor illness activity with real-time data.

to studythe clinical, dynamic and prognostic aspects of acute transient psychoticdisorders.

67 inpatients with acutepsychotic state which was developed for the first time, free of schizophreniasymptoms (23.0 F; F 23.3; 23.8 F; F 23.9 ICD − 10) were examined. Mean age ofthe patients: 31,7±11 years. Clinical and psychopathological, clinical follow-up, statistical methods were used. The follow-up period of observation lasted 6years from the moment of reduction of psychotic symptoms of the 1st psychotic episode.

Up-to-one-week ?sychoses were observed in 31 patients (46,3%), whereas prolongedpsychotic disorders (longer than 30 days) occurred with 7.5% (n=5). Criticalcoming out of psychosis occurred with 25 patients (37,3%), lytic variant ofreduction of psychotic symptoms was observed in 62,7 % of cases (n=42). Duringthe 6-year term, recurring psychotic attacks were observed in 21 patients(31,3%). One relapse of illness was observed in 57,1% of cases (12 patients outof 21). In 9 patients (42,9%), from 2 to 5 psychotic attacks were recorded. Allrecurring attacks of the disease were characterised by psychotic episodes ofschizophrenic patterns combined with specific deficit symptoms withinpostpsychotic period (autistic symptoms, decreased energetic potential ofindividuality, flattened affect, impaired abstract thinking).

theresults have enabled to identify 31,3% of 23.0 F cases as atypical beginning ofschizophrenic process, thus affording ground for maintenance therapy afterclinical reduction of the first psychotic episode. Lytic coming out of psychotic state revealed statisticallysignificant relationship with further relapse of the disease.

application of the evidence-based medicine in psychiatry undoubtedly is a basis of successful treatment of schizophrenia and emergence of new psychopharmacological data strengthens it. However noncritical perception of progress in psychopharmacology makes understanding of strategic objectives of schizophrenia’s treatment very oversimplified.

to define a position of psychiatrists about role of psychopharmacotherapy in structure of schizophrenia’s treatment at outpatients.

100 psychiatrists of an outpatient-clinic, medical documentation (of 570 outpatients with schizophrenia).

the standardized analysis of medical documentation; the structured interview which defined:

1. a) the knowledge of psychiatrists about neuroleptics

2. b) subjective criteria of neuroleptic choice

3. c) the doctor’s purposes in treatment of the outpatient with schizophrenia.

4. d) set of the therapeutic techniques applied by the doctor.

100% of doctors have basical knowledge about neuroleptics; 20% declared direct dependence of efficiency of shizophrenia’s treatment on “right choice” of preparation. In 80% of cases more critical relation to pharmacotherapy was defined, borders of its application were outlined, but only 15% confirmed these words in practice, using psychopharmacotherapy as ONE of instruments of treatment, equally with psychoeducation etc. Other's treatment consisted in “suitable” preparation or medicinal combinations searching; psychoeducation included only informing about medicine.

The tendency of substitution of the concept “treatment", as process of compensation (or restoration) the patient's premorbid status, by the concept “choice of the preparation with the proved efficiency” is traced in practice. Selection of the instrument of treatment turns into the treatment’s purpose that involves limitation of medical tactics and negative consequences for patients.

Clinical studies and practical use of amisulpride in Chinese population were rarely reported.

To evaluate the efficacy and safety profile of amisulpride in Chinese patients with schizophrenia.

To assess the change of the Positive and Negative Symptom Scale (PANSS) and adverse events emerged during the study.

In this national, prospective, open-label, multicenter, single arm study, 316 patients with ICD-10 diagnosis schizophrenia were treated with amisulpride for 8 weeks. The PANSS was primarily used for efficacy evaluation.

Of the 295 patients included for efficacy analysis, 66.8% reached a decrease of ≥50% PANSS total score at week 8. The mean (SD) baseline PANSS total score was 89.1 (13.7), as the study proceeded, the score decreased to 73.0 (17.7), 60.7 (17.6) and 51.0 (14.6) at week 2, 4 and 8 visits, respectively. The mean (SD) PANSS positive subscale score decreased from 23.8 (5.7) at baseline to 18.1 (6.2) at week 2, 14.1 (5.5) at week 4, and 11.1 (4.1) at week 8. The mean (SD) PANSS negative subscale score decreased from 23.7 (7.9) at baseline to 20.7 (8.0) at week 2, 17.8 (7.8) at week 4, and 15.2 (7.0) at week 8. All above measures were significantly improved at each post-baseline visit compared with baseline (P>0.05). Extrapyramidal disorder (25.9%) and blood prolactin increase (25.9%) were the most frequently reported adverse events, but the incidence of endocrine disorders (8.2%) was relatively low.

Amisulpride had both good clinical efficacy and safety profile for Chinese schizophrenic patients.

We have previously investigated the association between family history of psychosis and long-term outcome in schizophrenia in a systematic review and found no studies that focused on social outcome.

To study effect of family history on long-term occupational, social, clinical and global outcome in schizophrenia.

Aims: In this study we aimed to investigate how family history affects long-term occupational, social, clinical and global outcome in schizophrenia in a population-based cohort study.

Sixty nine persons with schizophrenia spectrum diagnosis from the Northern Finland Birth Cohort 1966 were examined at around 43 years of age, in average 17 years since onset of psychosis. A Strauss-Carpenter Outcome Scale –interview was conducted to gather information regarding occupational, social, clinical and global outcome. The family history of psychosis was examined based on register data and interviews.

Seventeen (24.6%) of the schizophrenia cases had family history of psychosis. The presence of family history of psychosis did not associate statistically significantly to occupational (FH+ vs FH-: mean 24.9 vs. 28.4; p = 0.470), social (34.5 vs. 33.2; p = 0.811), clinical (29.9 vs. 33.4; p = 0.510) or global outcome (22.2 vs. 22.7; p = 0.827).

This was the first original study on effects of family history of psychosis on long-term social outcome in schizophrenia. We did not find statistically significant association between family history of psychosis and long-term outcome in schizophrenia. Since the number of subjects with family history of psychosis was quite low, a study with larger sample size is desirable.

Some studies have shown that more than 40% of patients with first episode psychosis (FEP) are nonadherent and treatment with long – acting antipsychotics (LAIs) could increase their compliance. However, studies on efficacy of LAIs versus oral antipsychotics for preventing relapse among schizophrenia patients have produced conflicting results.

With this study we want to asses if patients with FEP in treatment with LAIs have a decreased incidence of readmission compared with patients in treatment with oral antipsychotics over 6 month follow – up.

188 FEP patients were consecutively admitted to Hospital del Mar since January 2008 to September 2014. The included evaluation was, among others: sociodemographic data, duration of untreated psychosis (DUP), diagnosis, substance use and clinical data at baseline. Later, antipsychotic treatment and number of admissions and of emergencies over 6 months were also recorded. We studied difference sin readmission, number of emergencies between patients on LAI and oral treatment.

We found a significative decreased incidence of readmission (p=0,000) and a lower number of emergencies (p=0,017) in the group of FEP patients treated with LAIs versus the group treated with oral antipsychotics.

In our sample, treatment with LAIs is associated with a reduced readmission rate and a lower number of emergencies in patients with FEP. This finding are agree with the results of other studies that show a significantly reduced relapse and a lowest risk of rehospitalization in FEP patients treated with LAIs.

Medication non-adherence is a major factorcontributing to poor clinical outcomes in patients with mental health disordersand is a complex behaviouralprocess determined by several interactingfactors. Patient adherence to treatment is likely to be influenced by a complexinteraction of treatment, patient beliefs and sociodemographic factors.

The aim of this study is to identify patient relatedfactors that affect adherence and assess the impact of attitudes and beliefs inmedication adherence.

This cross sectional study is being developed at Mental Health Departments of 3general hospitals in Lisbon great area. The sample is being collected through individual interviews. The participants will complete the Beliefsabout Medicines Questionnaire (Horneet al., 1997); Medication Adherence Questionnaire (Delgado & Lima, 2001) and additional measures to assess symptom severity, illness perception and sociodemographic characteristics.

We enrolled a total of 121 patients (mean age= 39.8; ± 9.3) withthe following diagnoses: schizophrenia(40.5%),schizo-affective(5.8%), bipolar disorder (50.4%) and other psychosis (3.3%). We have found a significant negative correlation withmedication beliefs and adherence (r=-0.226;p= 0.013) and a significant correlation with beliefs and psychopathology (r=0.41;p=0.00), i.e., patientswith negative beliefs and higher levels of psychopathology, less adhered tomedication.

Shared discussion of beliefs about medication betweenpatient and mental health professional allows wider exploration of personalmeanings that can help to improve medication adherence and therapeuticalliance. Further research on patients beliefs should focus on targeting non-adherent patientswhose reasons for their non-adherence is driven bytheir medication beliefs.

Schizophrenia is associated with an increased risk of sudden cardiac death, traditionally attributed to prolonged QTc interval and cardiovascular risk factors such as metabolic syndrome. However, defective ion channels are also implicated in schizophrenia. This applies as well for Brugada syndrome (BrS), a rare hereditary cardiac disorder associated with an increased risk of cardiac arrhythmias, which can been provoked by various drugs, including psychotropic.

To screen whether an increased prevalence of suspect Brugada ECG is present in patients with recent onset schizophrenia.

273 subjects with recent onset schizophrenia admitted between 2006 and 2012 and 306 healthy controls, underwent an ECG. All persons who had an ECG suspect for BrS were asked to undergo a provocation test to diagnose/exclude BrS. We checked whether patients had deceased during follow-up.

20/273 patients (7.3%) and 5/306 healthy controls (1.6%) showed an ECG suspect for BrS, with a Relative risk (RR) of 4.8 (p<0.001). Thus far 12 provocation tests have been performed, confirming BrS in three patients (1.1%). Ten patients had deceased during follow-up, of which two due to sudden cardiac death. Patients and controls didn’t differ significantly on average QTc interval.

Conclusion: This study shows that a considerable subset of patients with recent onset schizophrenia have an ECG suspect of Brugada Syndrome, confirming results in a population with chronic schizophrenia (Blom 2014). This may imply that there is a common pathophysiologic mechanism involved in both disorders. Screening for Brugada Syndrome in schizophrenia is relevant to prevent sudden cardiac death.

Though neurocognitive dysfunctions are common in schizophrenia, the course and predictors of change of cognition remain uncertain.

To understand the longitudinal changes and their predictors in cognition, which is important for the etiological investigation of schizophrenia.

Aims. To analyse if premorbid school performance, age of illness onset and the severity of illness predicts change in cognition in schizophrenia in a general population sample.

The sample included cases with schizophrenia spectrum disorder from the Northern Finland 1966 Birth Cohort. Data on school marks at age 16 yearsand severity of symptoms and occupational functioning around first episode and after years of illness were gained from national registers, hospital notes and interviews. Verbal and visual memory and executive functioning were measured twice, at ages 34 and 43 years. The number of cases varied in analyses from 29 to 41, depending on the analysed cognitive test.

Association between lower school marks at age 16-years and decrease in executive functioning (p=0.032) and visual learning and memory (p=0.039) was found, even when adjusted by age of illness onset and cognitive functioning at age 34-years. Change of cognition was not predicted by severity of symptoms nor occupational functioning. Male gender associated to decrease of executive functioning (p=0.032) and earlier age of illness onset to decrease of visual learning and memory (p=0.045).

School performance at age 16 years associates to later longitudinal change of cognition. Based on our results, later cognitive functioning may reflect the evolution of schizophrenia illness.

The effectiveness of systematic quality improvement initiatives in psychiatric care remains unclear.

To elucidate the adherence to recommended evidence-based guidelines in clinical practice.

To examine whether the quality of care among patients hospitalized with schizophrenia has changed following the implementation of a systematic monitoring and auditing program of hospital performance measures.

In a nationwide population-based cohort study, we identified 14,228 patients admitted to Danish psychiatric departments between 2004 and 2011 and registered in The Danish Schizophrenia Registry. The registry systematically monitors and audits the adherence to clinical guideline recommended processes of care at all Danish psychiatric hospital departments treating patients with schizophrenia.

The overall proportion of all relevant recommended processes of care delivered to the patients increased from 64 % to 76 % between 2004 and 2011. The adherence to a number of individual processes of care increased over time, including assessment of psychopathology using a diagnostic interview (Relative risk (RR) 2.01, 95 % CI: 1.50; 2.69), contact with relatives (RR 1.44, 95 % CI: 1.27; 1.62), psychoeducation (RR 1.33, 95 % CI: 1.18; 1.48), psychiatric aftercare (RR 1.06 95 % CI: 1.01; 1.11) and suicide risk assessment (RR 1.31, 95 % CI: 1.20; 1.43). However, improvements were not observed for all assessed processes of care and substantial variation remained between the hospitals.

Quality of care improved substantially from 2004 to 2011 among patients hospitalized with schizophrenia at Danish hospitals. However, continued efforts to reduce performance variation between hospitals are warranted.

A continuum perspective to understand persecutory delusions suggests that non-clinical persecutory ideations are at the mild end on the same spectrum of persecutory delusions. Based on clinical studies, reasoning biases such as 'jumping to conclusions' (JTC) style, attributional biases (AB), and Theory of Mind (ToM) deficit have been suggested as cognitive risk factors of persecutory delusions, with most robust evidence for JTC. Consistent with the continuum perspective, it is of interest whether these reasoning biases are risk factors of persecutory ideations in the non-clinical population as well.

To examine the association between JTC, AB, ToM deficit, and persecutory ideations in non-clinical populations.

To test the following hypotheses:

1. 1. JTC, AB, and ToM deficit will be found in individuals with non-clinical persecutory ideations.

2. 2. Among the three biases, JTC will be more strongly associated with the severity of persecutory ideations in the non-clinical population.

Twenty studies from 2001 to 2013 analyzing the relationship between reasoning biases and severity of persecutory ideations in non-clinical populations were systematically reviewed.

JTC, AB and ToM deficit were found in individuals with non-clinical persecutory thinking but at reduced levels of severity as compared to the clinical populations. A consistent association between JTC and non-clinical persecutory thinking was found across studies. However, studies of AB and ToM deficit yielded conflicting findings.

Current findings confirm the role of JTC in the pathogenesis of persecutory delusions, and support the development of early interventions targeting data-gathering for individuals at risk of developing persecutory delusions.

Patients with schizophrenia have lower IQ as compared to the general population. Furthermore, cognitive decline has been observed even before the onset of the first episode psychosis. Whether premorbid functioning and IQ also predict long-term remission status is not yet known.

1057 patients with schizophrenia and related disorders were included in GROUP project. Premorbid Adjustment Scale (PAS), IQ and Positive and Negative Symptom Scale (PANSS) were obtained at inclusion. After 6 years 691 patients were re-examined. On 530 patients we were able to determine remission status using the PANSS remission tool. Patients were divided into two groups; those who were in remission (Rem) and those who were not (NR). Groups were compared on PAS and IQ using independent sample t-tests groups.

Analyses revealed that patients who dropped out during the follow-up of 6 years had lower IQ, and higher PANSS scores as compared to those who were remained in the study. After 6 years 58% of patients were in remission. Remission status after 6 years was associated with IQ and premorbid adjustment in childhood and adolescence at inclusion.

Poorer premorbid adjustment and lower IQ at baseline are associated with non-remission after 6 years. This suggests that in order to improve the course and outcome of schizophrenia, one should aim to detect and intervene well before the first psychotic symptoms arise.

Although antipsychotics are widely prescribed, their effect of on improving poor illness insight in schizophrenia has seldom been investigated and therefore remains uncertain. This paper examines the effects of low dose haloperidol, amisulpride, olanzapine, quetiapine, and ziprasidone on insight in first-episode schizophrenia, schizoaffective disorder, or schizophreniform disorder.

The effects of five antipsychotic drugs in first episode psychosis on insight were compared in a large scale open randomized controlled trial conducted in fourteen European countries: the European First-Episode Schizophrenia Trial (EUFEST). Patients with at least minimal impairments in insight were included in the present study (n=455). Insight was assessed with item G12 of the Positive and Negative Syndrome Scale (PANSS), administered at baseline and at 1, 3, 6, 9, and 12 months after randomization.

The use of antipsychotics was associated with clear improvements in insight, independent of other symptoms. This effect was most pronounced in the first three months of treatment, with quetiapine being significantly less effective than other drugs.

Use of antipsychotics was associated with an improvement in insight, over and above their effects on other symptoms of schizophrenia. Effects of spontaneous improvement cannot be ruled out due to the lack of a placebo control group, although such a large spontaneous improvement seems unlikely. Notably, the improvement of insight was less pronounced for quetiapine compared to haloperidol, amisulpride, olanzapine, quetiapine, and ziprasidone.

Studies in the general population show cannabis use has a beneficial effect on metabolic disorders. Given the increased cardiometabolic risk in patients with psychotic disorders, as well as their prevalent use of cannabis, we aim to investigate whether such effects are also evident in these patients.

3176 patients with chronic psychotic disorders from mental health institutions in the Netherlands were included in the study. With multivariate regression analyses we examined the effects of cannabis use on metabolic risk factors; BMI, waist circumference, blood pressure (BP), cholesterol, HDL-C, LDL-C, triglycerides, glucose and HbA1c. Age, sex, smoking, alcohol use and antipsychotic drugs were included as confounders. Next, we examined change in metabolic risk factors after one-year follow up for cannabis users, non-users, discontinuers and starters.

We found a significant negative association between cannabis use and BMI (p=0.003), waist circumference (p>0.001), diastolic BP (p=0.015) and HbA1c (0.004). One year later, patients who had discontinued their cannabis use had a greater increase of BMI (p=0.002) and waist circumference (p=0.011) than other patients. They also had a greater increase of diastolic BP than non-users (p=0.036) or starters (p=0.004).

Discontinuation of cannabis use increased metabolic risk. To stop cannabis use is often an important treatment goal, because it reduces psychotic symptoms. However, physicians should be aware of the increased metabolic risk in patients who discontinue the use of cannabis. Extra attention should be paid to monitoring and treatment of metabolic parameters in these patients to prevent cardiovascular diseases and premature cardiovascular mortality.

Alcohol and other substance use problems are common among individuals with schizophrenia.

Many of the previous studies have focused on clinical comorbidity, not on longitudinal design.

The aim of this study was to investigate if premorbid or early substance use predicts long-term clinical and social course in schizophrenia.

A systematic review to identify potentially relevant studies was conducted. Studies with a follow-up period of at least two years were included. Following outcomes were studied: negative, positive and total symptoms, clinical remission, hospitalizations, social functioning, employment, and global outcome. Spearman's correlations were used to summarize results, negative correlations indicating poorer outcome with substance use.

The search identified 10776 unique potentially relevant articles of which 25 studies met our inclusion criteria. The meta-analysis included 5 to 13 studies in each outcome category. Moderate to high heterogeneity was found between studies in each outcome group. In meta-analysis, substance use associated modestly with outcome. All the associations were non-significant and correlations between −0.06 and 0.09. Non-significant findings are explained by the fact that the original studies found often opposite results, indicating both worse and better long-term outcome for early substance users.

Although comorbid substance use associates with poorer outcome in schizophrenia, the early substance use has only a modest effect on long-term outcome. This difference to studies on current comorbidity may indicate that those who continue substance abuse have poor outcome, e.g. due to poor treatment adherence, whereas those who stop the abuse may have relatively good outcome.

Cariprazine, a dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors, is being developed for the treatment of schizophrenia

To explore the effect of cariprazine on negative symptoms of schizophrenia.

Subjects aged 18-60 years with acute schizophrenia, current acute episode >2 weeks, and a PANSS total score ≥80 and ≤120 were randomly allocated in a 6-Week study NCT01104766 to cariprazine 3 mg/d, cariprazine 6 mg/d, aripiprazole 10 mg/d (active control), or placebo [1]. Post–hoc analyses were performed on subjects with severe negative symptoms and low-to-moderate positive symptoms, defined according to Marder.

Data of 26 subjects were included in the cariprazine 3 mg/d (17.2% of the total sample), 34 in the cariprazine 6 mg/d (22.1%), 35 in the aripiprazole (23.3%) and 35 in the placebo (23.5%) groups, respectively. Change from baseline to Week 6 in the PANSS Factor Score for Negative Symptoms (PFSNS) was statistically significant for cariprazine 6 mg/d versus placebo (least squares mean difference: cariprazine 3 mg/d=-2.15, p= 0.20; cariprazine 6 mg/d = −3.68, p=.019). Cariprazine 6 mg/d was superior to placebo at each weekly assessment from Week 3. The changes in PFSNS for aripiprazole were not statistically significant at any weekly assessment.

Post–hoc analyses performed on subjects with acute schizophrenia, high level of negative symptoms and low-to-moderate positive symptoms, showed that the patients in the cariprazine 6 mg/d group had a significantly greater improvement relative to placebo on the PFSNS.

Accumulating evidence indicates concordant epigenetic dysregulation in the brain and peripheral blood leukocytes in schizophrenia. It has also been found that stressful and traumatic events may alter DNA methylation; however, such studies have not been performed in schizophrenia patients.

This study aimed at comparing LINE-1 methylation in first-episode schizophrenia (FES) patients and healthy control (HC) subjects with respect to the history of trauma.

We recruited 40 FES patients and 49 HC subjects matched for age, gender and body mass index (BMI). The early trauma self-report – short form (ETISR-SF) was administered to assess traumatic events. In addition to assessment of LINE-1 methylation, serum levels of homocysteine, folate and vitamin B12 were measured in all subjects.

There was no significant difference in LINE-1 methylation between FES patients and HC subjects. However, LINE-1 methylation was significantly lower in FES patients with positive history of trauma when compared with FES patients and HC subjects with negative history of trauma (58.08±3.27% vs. 61.28±4.12%, p = 0.022 and 58.08±3.27% vs. 61.12±4.73%, p = 0.038, respectively). There was no significant difference in LINE-1 methylation between FES patients and HC subjects with negative history of trauma. There was a negative correlation between total trauma score and LINE-1 methylation (r = −0.390, p = 0.012). After controlling for confounding variables (age, gender, treatment duration, pack-year index, metabolic parameters), LINE-1 methylation was associated with total trauma score (p = 0.011).

Traumatic events might be associated with lower global DNA methylation in FES patients.