Progranulin Gene Variability and Plasma Levels in Bipolar Disorder and Schizophrenia

Basing on the assumption that frontotemporal lobar degeneration (FTLD), schizophrenia and bipolar disorder (BPD) might share common aetiological mechanisms, we analyzed genetic variation in the FTLD risk gene progranulin (GRN) in a German population of patients with schizophrenia (n = 271) or BPD (n = 237) as compared with 574 age-, gender- and ethnicity-matched controls. Furthermore, we measured plasma progranulin levels in 26 German BPD patients as well as in 61 Italian BPD patients and 29 matched controls

Regulation of gene transcription in bipolar disorders: Role of DNA methylation in the relationship between prodynorphin and brain derived neurotrophic factor

Bipolar Disorder (BD) is a prevalent and disabling condition, determined by gene-environment interactions, possibly mediated by epigenetic mechanisms. The present study aimed at investigating the transcriptional regulation of BD selected target genes by DNA methylation in peripheral blood mononuclear cells of patients with a DSM-5 diagnosis of type I (BD-I) and type II (BD-II) Bipolar Disorders (n = 99), as well as of healthy controls (CT, n = 42). The analysis of gene expression revealed prodynorphin (PDYN) mRNA levels significantly reduced in subjects with BD-II but not in those with BD-I, when compared to CT. Other target genes (i.e. catechol-O-methyltransferase (COMT), glutamate decarboxylase (GAD67), serotonin transporter (SERT) mRNA levels remained unaltered. Consistently, an increase in DNA methylation at PDYN gene promoter was observed in BD-II patients vs CT. After stratifying data on the basis of pharmacotherapy, patients on mood-stabilizers (i.e., lithium and anticonvulsants) were found to have lower DNA methylation at PDYN gene promoter. A significantly positive correlation in promoter DNA methylation was observed in all subjects between PDYN and brain derived neurotrophic factor (BDNF), whose methylation status had been previously found altered in BD. Moreover, among key genes relevant for DNA methylation establishment here analysed, an up-regulation of DNA Methyl Transferases 3b (DNMT3b) and of the methyl binding protein MeCP2 (methyl CpG binding protein 2) mRNA levels was also observed again just in BD-II subjects. A clear selective role of DNA methylation involvement in BD-II is shown here, further supporting a role for BDNF and its possible interaction with PDYN. These data might be relevant in the pathophysiology of BD, both in relation to BDNF and for the improvement of available treatments and development of novel ones that modulate epigenetic signatures

Italian patients with more recent onset of Major Depressive Disorder have a shorter duration of untreated illness

Background: Previous investigation on the duration of untreated illness (DUI) in patients with Major Depressive Disorder (MDD) revealed a different latency to first antidepressant treatment, with adverse consequences in terms of outcome for individuals with a longer DUI. Recent reports, moreover, documented a reduced DUI, as observed with the passage of time, in patients with different psychiatric disorders. Hence, the present study was aimed to assess DUI and related variables in a sample of Italian patients with MDD as well as to investigate potential differences in subjects with onset before and after 2000. Methods: An overall sample of 188 patients with MDD was assessed through a specific questionnaire investigating DUI and other variables related to the psychopathological onset and latency to first antidepressant treatment, after dividing them in two different subgroups on the basis of their epoch of onset. Results: The whole sample showed a mean DUI of approximately 4.5 years, with patients with more recent onset showing a significantly shorter latency to treatment compared with the other group (27.1\ub142.6 vs 75.8\ub1105.2 months, P<.05). Other significant differences emerged between the two subgroups, in terms of rates of onset-related stressful events and benzodiazepine prescription, respectively, higher and lower in patients with more recent onset. Conclusions: Our findings indicate a significant DUI reduction in MDD patients whose onset occurred after vs before 2000, along with other relevant differences in terms of onset-related correlates and first pharmacotherapy. Further studies with larger samples are warranted to confirm the present findings in Italy and other countries

Allelic and genotype frequencies given as %(n) in German cases compared with age-, gender- and ethnicity matched controls.

*<p><i>P</i><0.001, OR: 0.20, 95%CI: 0.09–0.14.</p>**<p><i>P</i> = 0.001, OR: 0.60, 95%CI: 0.44–0.81.</p>***<p><i>P</i> = 0.0002, OR: 0.35, 95%CI: 0.20–0.61.</p>****<p><i>P</i><0.001, OR: 0.28, 95%CI: 0.17–0.44.</p>*****<p><i>P</i><0.001, OR: 0.63, 95%CI: 0.49–0.80.</p>°<p><i>P</i> = 0.0003, OR: 0.37, 95%CI: 0.22–0.63.</p>°°<p><i>P</i> = 0.01, OR: 0.66, 95%CI: 0.49–0.90.</p>°°°<p><i>P</i> = 0.002, OR: 0.48, 95%CI: 0.31–0.77.</p>°°°°<p><i>P</i><0.001, OR: 0.43, 95%CI: 0.30–0.63.</p>°°°°°<p><i>P</i> = 0.005, OR: 0.70, 95%CI: 0.55–0.89.</p>•<p><i>P</i> = 0.01, OR: 0.51, 95%CI: 0.30–0.85.</p>••<p><i>P</i><0.0001, OR: 0.53, 95%CI: 0.39–0.72.</p>•••<p><i>P</i> = 0.019, OR: 0.62, 95%CI: 0.42–0.91.</p>••••<p><i>P</i> = 0.007, OR: 0.71, 95%CI: 0.56–0.91.</p

Characteristics of Italian (I) and German (G) subjects included in plasma level evaluation.

<p>Characteristics of Italian (I) and German (G) subjects included in plasma level evaluation.</p

Characteristics of German individuals included in the association study.

*<p> <b>age at disease onset.</b></p

Scattergram of progranulin plasma levels in BPD patients and controls.

<p>Black lines represent mean values. G = German. I = Italian. *<i>P</i><0.001, patients versus controls.</p

The influence of illness-related variables, personal resources and context-related factors on real-life functioning of people with schizophrenia

In people suffering from schizophrenia, major areas of everyday life are impaired, including independent living, productive activities and social relationships. Enhanced understanding of factors that hinder real-life functioning is vital for treatments to translate into more positive outcomes. The goal of the present study was to identify predictors of real-life functioning in people with schizophrenia, and to assess their relative contribution. Based on previous literature and clinical experience, several factors were selected and grouped into three categories: illness-related variables, personal resources and context-related factors. Some of these variables were never investigated before in relationship with real-life functioning. In 921 patients with schizophrenia living in the community, we found that variables relevant to the disease, personal resources and social context explain 53.8% of real-life functioning variance in a structural equation model. Neurocognition exhibited the strongest, though indirect, association with real-life functioning. Positive symptoms and disorganization, as well as avolition, proved to have significant direct and indirect effects, while depression had no significant association and poor emotional expression was only indirectly and weakly related to real-life functioning. Availability of a disability pension and access to social and family incentives also showed a significant direct association with functioning. Social cognition, functional capacity, resilience, internalized stigma and engagement with mental health services served as mediators. The observed complex associations among investigated predictors, mediators and real-life functioning strongly suggest that integrated and personalized programs should be provided as standard treatment to people with schizophrenia