M.C. Palazzo

Selective DNA Methylation of BDNF Promoter in Bipolar Disorder: Differences Among Patients with BDI and BDII

The etiology of bipolar disorder (BD) is still poorly understood, involving genetic and epigenetic mechanisms as well as environmental contributions. This study aimed to investigate the degree of DNA methylation at the promoter region of the brain-derived neurotrophic factor (BDNF) gene, as one of the candidate genes associated with major psychoses, in peripheral blood mononuclear cells isolated from 94 patients with BD (BD I=49, BD II=45) and 52 healthy controls. A significant BDNF gene expression downregulation was observed in BD II 0.53±0.11%; P<0.05), but not in BD I (1.13±0.19%) patients compared with controls (CONT: 1±0.2%). Consistently, an hypermethylation of the BDNF promoter region was specifically found in BD II patients (CONT: 24.0±2.1%; BDI: 20.4±1.7%; BDII: 33.3±3.5%, P<0.05). Of note, higher levels of DNA methylation were observed in BD subjects on pharmacological treatment with mood stabilizers plus antidepressants (34.6±4.2%, predominantly BD II) compared with those exclusively on mood-stabilizing agents (21.7±1.8%; P<0.01, predominantly BD I). Moreover, among the different pharmacological therapies, lithium (20.1±3.8%, P<0.05) and valproate (23.6±2.9%, P<0.05) were associated with a significant reduction of DNA methylation compared with other drugs (35.6±4.6%). Present findings suggest selective changes in DNA methylation of BDNF promoter in subjects with BD type II and highlight the importance of epigenetic factors in mediating the onset and/or susceptibility to BD, providing new insight into the mechanisms of gene expression. Moreover, they shed light on possible mechanisms of action of mood-stabilizing compounds vs antidepressants in the treatment of BD, pointing out that BDNF regulation might be a key target for their effects.

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-naïve 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.

Reduced treatment-emergent sexual dysfunction as a potential target in the development of new antidepressants

Pleasurable sexual activity is an essential component of many human relationships, providing a sense of physical, psychological, and social well-being. Epidemiological and clinical studies show that depressive symptoms and depressive illness are associated with impairments in sexual function and satisfaction, both in untreated and treated patients. The findings of randomized placebo-controlled trials demonstrate that most of the currently available antidepressant drugs are associated with the development or worsening of sexual dysfunction, in a substantial proportion of patients. Sexual difficulties during antidepressant treatment often resolve as depression lifts but can endure over long periods and may reduce self-esteem and affect mood and relationships adversely. Sexual dysfunction during antidepressant treatment is typically associated with many possible causes, but the risk and type of dysfunction vary with differing compounds and should be considered when making decisions about the relative merits and drawbacks of differing antidepressants. A range of interventions can be considered when managing patients with sexual dysfunction associated with antidepressants, including the prescription of phosphodiesterase-5 inhibitors, but none of these approaches can be considered “ideal.” As treatment-emergent sexual dysfunction is less frequent with certain drugs, presumably related to differences in their pharmacological properties, and because current management approaches are less than ideal, a reduced burden of treatment-emergent sexual dysfunction represents a tolerability target in the development of novel antidepressants.

Health literacy about pharmacological treatment in anxiety disorders: a systematic review

Anxiety disorders are treatable conditions, but many affected individuals neither seek professional help nor adhere to recommended pharmacological treatments. Increasing the health literacy of people with (or at risk of) anxiety disorders may encourage treatment‐seeking and adherence to recommended interventions. Aims of this study were to review the literature relating to health literacy in the treatment of anxiety disorders, focusing on results on public opinion on psychotropic medications and its effectiveness in improving access to psychiatric health care and the actual use of medications.

Vagus nerve stimulation in treatment-resistant depression: acute and follow-up results of an italian case series.

Abstract The present study evaluated short- and long-term efficacy and tolerability of augmentative vagus nerve stimulation (VNS) in a group of patients with treatment-resistant depression (N = 6). A statistically significant improvement in the Hamilton Depression Rating Scale (HDRS21) and Montgomery-Asberg Depression Rating Scale after 3 months (P = 0.039 and P = 0.05, respectively) was found in comparison with baseline (VNS implant). After 12 months, a statistically significant improvement was observed in the Hamilton Depression Rating Scale (HDRS21), Montgomery-Asberg Depression Rating Scale, and Clinical Global Impression (P = 0.01, P = 0.005, and P = 0.001, respectively). Patients showed an overall favorable tolerability. Present data support VNS short- and long-term efficacy and tolerability in a small group of patients with treatment-resistant depression. Further controlled investigation is necessary to confirm the present open findings.

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

&NA; 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. HighlightsSelective target genes expression alterations in BDRole of DNA methylation in mediating PDYN mRNA level changes in BDCorrelation between PDYN and BDNF epigenetic mark in BD

Access and latency to first antipsychotic treatment in Italian patients with schizophrenia and other schizophrenic spectrum disorders across different epochs.

The duration of untreated illness (DUI) is a measure to express the latency to first psychopharmacological treatment: it differs among psychiatric disorders, being influenced by several illness‐intrinsic and environmental factors. The present study aimed to assess differences in DUI and related variables in patients with schizophrenia (SKZ) versus other schizophrenic spectrum disorders (SSDs) across different epochs.

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

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.

Use of asenapine as add-on therapy in the treatment of bipolar disorder: a comprehensive review and case series

Introduction: Several randomized controlled trials (RCTs), conducted in schizophrenic and bipolar patients, have documented the efficacy and tolerability of asenapine as monotherapy both for short- and long-term treatment. However, evidence on its augmentative use is more limited and related to the manic/mixed phase of bipolar disorder (BD). Areas covered: The present article reviews augmentative asenapine efficacy and safety/tolerability in the treatment of BD. It also includes some original cases of bipolar patients treated with add-on asenapine in the short- and long-term. Expert opinion: To date, only a single RCT with manic/mixed patients with partial response to mood-stabilizer monotherapy supports the efficacy and safety/tolerability of augmentative asenapine to lithium/valproate, both in acute and long-term treatment. Additionally, two case reports confirm the overall effectiveness of augmentative asenapine to clozapine and valproate. Our case series, consisting of 4 bipolar patients treated with adjunctive asenapine to mood stabilizers and atypical antipsychotics – with treatment duration ranging from 1 to 14 months – provided clinical results that are consistent with literature data. Taken as a whole, available evidence seems to support the efficacy and safety of adjunctive asenapine in bipolar patients, though additional studies with active comparators are requested to confirm the current body of evidence.

P.1.a.024 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 agematched, healthy controls were recruited. BDNF methylation levels from peripheral blood mononuclear cells (PBMCs) were compared by analysis of variance followed by Bonferronis 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 (Po0.01). When stratified on the basis of mood status, methylation levels of depressed patients were significantly higher, compared to the levels of manic/mixed patients (Po0.01). 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-naive 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. & 2014 Elsevier B.V. All rights reserved. 1. Objectives of the study and background Major Depressive Disorder (MDD) and Bipolar Disorder (BD) are prevalent, recurring and highly disabling conditions, etiologically determined by gene–environment interactions (Tsuang and Faraone, 1990; Craddock and Jones, 2001). Discriminating between bipolar and unipolar depression, as well as between bipolar I and II patients, remains a diagnostic challenge, with clinical consequences in terms of treatment selection and outcome. Among genes potentially implicated in the pathophysiology of mood disorders, the brain derived neurotrophic factor (BDNF) gene has been extensively investigated over the last few years, being associated with neural adaptations (neuronal development, proliferation and survival, synaptic plasticity) occurring in different contexts (Duman et al., 2000; Nakata et al., 2003). Indeed, among processes modulating gene expression in the central nervous system, epigenetic mechanisms represent a link between gene expression alterations and environmental factors: they can contribute to phenotypic effects and,