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

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Epigenetic modulation of BDNF gene: Differences in DNA methylation between unipolar and bipolar patients

Background The brain derived neurotrophic factor (BDNF) gene and its epigenetic regulation have been repeatedly implicated in the pathophysiology of mood disorders. Following previous investigation in the field, we further investigated differences in BDNF promoter gene methylation in patients with mood disorders, comparing unipolar and bipolar subjects, on the basis of illness phase, gender, age and psychotropic prescription. Methods 154 patients (43 MDD; 61 BD I; 50 BD II), on stable pharmacological treatment, and 44 age-matched, healthy controls were recruited. BDNF methylation levels from peripheral blood mononuclear cells (PBMCs) were compared by analysis of variance followed by Bonferroni's post-hoc test. Results Similar, higher levels of BDNF gene promoter methylation were found in BD II and MDD patients, compared to BD I subjects (P<0.01). When stratified on the basis of mood status, methylation levels of depressed patients were significantly higher, compared to the levels of manic/mixed patients (P<0.01). While gender and age did not seem to influence methylation levels of BDNF gene promoter, patients on lithium and valproate showed overall lower levels. Limitations: Cross-sectional analysis using PBMCs with further investigation with larger samples, including drug-na\uefve patients, needed to replicate findings in neuronal cells. Conclusions Present data confirm our previous results of higher methylation levels in BD II (compared to BD I) and MDD patients (compared to controls). A closer relationship between BD II and MDD, compared to BD I patients as well an association of lower methylation levels with the presence of mania/mixed state, compared to the depressive phase, was observed

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