Bernardo Dell'Osso

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.

Immuno-inflammatory, oxidative and nitrosative stress, and neuroprogressive pathways in the etiology, course and treatment of schizophrenia

In recent decades, a significant role for altered immunoinflammatory, oxidative and nitrosative stress (IO&NS) pathways in schizophrenia has been recognized (Smith and Maes, 1995; Wood et al., 2009). Importantly, such processes have provided crucial clues to the etiology, course and management of this devastating disorder. This is the focus of this special edition. Epidemiological findings supporting a role for prenatal viral, bacterial and protozoan infections in the etiology of schizophrenia have provided a seminal contribution to the neurodevelopmental hypothesis of schizophrenia (Brown and Derkits, 2010). The early developmental etiology of schizophrenia to a lesser extent has been focused on decreased vitamin D in early development, including via vitamin D modulation of the immune response to infection (McGrath et al., 2003). Interactions between these factors is suggested by the fact that vitaminDhas a documented role in immunemodulation, especially during placental development and in early childhood (Battersby et al., 2012; Liu et al., 2011). The maximal risk period for maternal infection association with offspring schizophrenia is shown to be early pregnancy (Brown et al., 2004; Khandaker et al., 2012). Interestingly many schizophrenia susceptibility genes are regulated by hypoxia, suggesting close interactions among IO&NS genes and obstetric complications leading to enhanced risk of schizophrenia (Nicodemus et al., 2008; Schmidt-Kastner et al., 2006). Other conditions of pregnancy, including hypoxia associated preeclampsia (Kendell et al., 1996), also increase the risk of the offspring being classed as having schizophrenia, emphasizing the profound impact of prenatal events. The evidence for the role of prenatal infection, both epidemiological and experimental, is excellently reviewed byUrsMeyer (2013–this issue) who has published extensively in this area. Many of the developmental effects of infection are driven not only by O&NS and proinflammatory cytokine increases in the placenta and fetus, but also by associated hypoferremia and zinc deficiency (Ganz and Nemeth, 2009; Prasad, 2009). Such changes render the offspring prone to subsequent second hits over the course of post-natal development, contributing to both the emergence and progression of disease manifestations. This is an important area of experimental research given that the elimination of the effects of maternal infection is estimated to decrease the incidence of schizophrenia by as much as 46% (Brown and Derkits, 2010).

Interactions between transcranial direct current stimulation (tDCS) and pharmacological interventions in the Major Depressive Episode: Findings from a naturalistic study

BACKGROUND Transcranial direct current stimulation (tDCS) is a non-invasive, neuromodulatory technique with an emerging role for treating major depression. OBJECTIVE To investigate the interactions between tDCS and drug therapy in unipolar and bipolar depressed patients who were refractory for at least one pharmacological treatment. METHODS This was a naturalistic study using data from 54 female and 28 male patients (mean age of 54 years) that consecutively visited our psychiatric unit. They received active tDCS (five consecutive days, 2mA, anodal stimulation over the left and cathodal over the right dorsolateral prefrontal cortex, twice a day, 20minutes). The outcome variable (mood) was evaluated using the Beck Depression Inventory (BDI) and the Hamilton Depression Rating Scale (HDRS). Predictor variables were age, gender, disorder and pharmacological treatment (seven dummy variables). We performed univariate and multivariate analyses as to identify predictors associated to the outcome. RESULTS After 5 days of treatment, BDI and HDRS scores decreased significantly (29%±36%, 18%±9%, respectively, P<0.01 for both). Benzodiazepine use was independently associated with a worse outcome in both univariate (β=4.92, P<0.01) and multivariate (β=5.8, P<0.01) analyses; whereas use of dual-reuptake inhibitors positively changed tDCS effects in the multivariate model (β=-4.7, P=0.02). A similar trend was observed for tricyclics (β=-4, P=0.06) but not for antipsychotics, non-benzodiazepine anticonvulsants and other drugs. CONCLUSION tDCS over the DLPFC acutely improved depressive symptoms. Besides the inherent limitations of our naturalistic design, our results suggest that tDCS effects might vary according to prior pharmacological treatment, notably benzodiazepines and some antidepressant classes. This issue should be further explored in controlled studies.

Meta-Review of Metanalytic Studies with Repetitive Transcranial Magnetic Stimulation (rTMS) for the Treatment of Major Depression

Background: Major Depression (MD) and treatment-resistant depression (TRD) are worldwide leading causes of disability and therapeutic strategies for these impairing and prevalent conditions include pharmacological augmentation strategies and brain stimulation techniques. In this perspective, repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique with a favorable profile of tolerability which, despite being recently approved by the Food and Drug Administration (FDA) for the treatment of patients with medication-refractory unipolar depression, still raises some doubts about most effective parameters of stimulation. Methods: A literature search was performed using PubMed for the years 2001 through February 2011 in order to review meta-analytic studies assessing efficacy and safety issues for rTMS in depressive disorders. Fifteen meta-analyses were identified and critically discussed in order to provide an updated and comprehensive overview of the topic with specific emphasis on potentially optimal parameters of stimulation. Results: First meta-analyses on the efficacy of rTMS for the treatment of MD and TRD have shown mixed results. On the other hand, more recent meta-analytic studies seem to support the antidepressant efficacy of the technique to a greater extent, also in light of longer periods of stimulation (e.g. > 2 weeks). Conclusion: rTMS seems to be an effective and safe brain stimulation technique for the treatment of medication refractory depression. Nevertheless, further studies are needed to better define specific stimulation-related issues, such as duration of treatment as well as durability of effects and predictors of response.

Age at onset and latency to treatment (duration of untreated illness) in patients with mood and anxiety disorders: A naturalistic study

This study was designed to investigate and compare demographic and clinical features with specific emphasis on age at onset, age at first treatment and, in particular, on duration of untreated illness (DUI), in patients with different mood and anxiety disorders. Study sample included 729 outpatients with the following diagnoses: major depressive disorder (n=181), bipolar disorder type I (BD I, n=115) and II (BD II, n=186), generalized anxiety disorder (n=100), panic disorder (n=96), and obsessive–compulsive disorder (n=51). Main demographic and clinical variables of the sample were compared among the diagnostic groups using one-way analysis of variance or χ2 tests. The diagnostic groups showed significant differences in relation to age at onset and age at first pharmacological treatment and in relation to latency to treatment. In particular, patients with major depressive disorder showed the shortest DUI (39.08 months), whereas patient with BD II showed the longest DUI (97.2 months) in comparison with the other groups. Within the group with anxiety disorders (F=7.512, P<0.001), patients with panic disorder showed the shortest DUI (44.35 months), whereas patients with obsessive–compulsive disorder showed the longest DUI (90.57 months). The present findings suggest that patients with different mood and anxiety disorders show significant differences in terms of age at onset, age at first treatment and, consequently, DUI, which potentially reflect different reasons influencing treatment delay.

Serotonin norepinephrine reuptake inhibitors (SNRIs) in anxiety disorders: a comprehensive review of their clinical efficacy

Anxiety disorders are common psychiatric conditions that typically require long‐term treatment. This review summarizes current knowledge of the pharmacological treatment of anxiety disorders with serotonin norepinephrine reuptake inhibitors (SNRIs) with specific emphasis on the findings of recent randomized clinical trials and relevant neurobiological investigations. It is now well established that gabaergic, noradrenergic and serotonergic systems play a critical role in the pathophysiology of anxiety disorders, abnormalities in these systems being related to structural and functional alterations in specific brain areas such as the amygdala, prefrontal cortex, locus coeruleus and hippocampus, as repeatedly shown by neuroimaging studies. SNRIs selectively inhibit norepinephrine and serotonin reuptake and have shown to be efficacious and generally well tolerated treatments in patients with anxiety disorders, with some potential clinical advantages over selective serotonin reuptake inhibitors (SSRIs), which are considered by many to represent first‐line pharmacological treatments in patients with anxiety disorders. Anxiety disorders are characterized by a typically chronic course, high rates of comorbidity and frequent partial response to standard treatments, and the increasing use of SNRIs reflects currently unmet clinical need, in terms of overall response, remission rates and treatment tolerability. Copyright

Neurodevelopment and inflammatory patterns in schizophrenia in relation to pathophysiology

As for other major psychoses, the etiology of schizophrenia still remains poorly understood, involving genetic and epigenetic mechanisms, as well as environmental contributions. In addition, immune alterations have been widely reported in schizophrenic patients, involving both the unspecific and specific pathways of the immune system, and suggesting that infectious/autoimmune processes play an important role in the etiopathogenesis of the disorder. Cytokines, in particular, are supposed to play a critical role in infectious and inflammatory processes, mediating the cross-talk between the brain and the immune system. In this perspective, even though mixed results have been reported, it seems that schizophrenia is associated with an imbalance in inflammatory cytokines. Alterations in the inflammatory and immune systems, moreover, seem to be already present in the early stages of schizophrenia and connected to the neurodevelopmental hypothesis of the disorder, identifying its roots in brain development abnormalities that do not manifest themselves until adolescence or early adulthood. At the same time, neuropathological and longitudinal studies in schizophrenia also support a neurodegenerative hypothesis and, more recently, a novel mixed hypothesis, integrating neurodevelopmental and neurodegenerative models, has been put forward. The present review aims to provide an updated overview of the connections between the immune and inflammatory alterations and the aforementioned hypotheses in schizophrenia.

Cytokine Polymorphisms in the Pathophysiology of Mood Disorders

INTRODUCTION An increasing amount of data suggests that dysregulation of the immune system, including the cytokine network, is associated with the etiology and pathophysiology of mood disorders. Genes encoding cytokines are highly polymorphic and single nucleotide polymorphisms, associated with increased or reduced cytokine production, have been described. The aim of this study was to define the genetic immunologic scenario associated with major depressive disorder (MDD) and bipolar disorder. METHODS Eighty-four Italian outpatients affected by bipolar disorder type I, bipolar disorder type II, or MDD, and 363 healthy controls were enrolled into the study. We analyzed allele and genotype distribution of -308 (G/A) tumor necrosis factor-a (TNF-a), +874 (T/A) interferon-g (IFN-g), -174 (G/C) interleukin (IL)-6, and -1082 (G/A) IL-10 promoter polymorphisms by Polymerase Chain Reaction Sequence Specific Primers technique. RESULTS We observed different genotype and allele distributions of TNF-a, IFN-g, and IL-10 polymorphisms in the three groups of patients analyzed. In particular, bipolar II patients were characterized by an absence of adenine (A) high producer allele of TNF-a (P<.001) and a lower percentage of TT high producer genotype of IFN-g (P<.001); bipolar I individuals showed reduced percentage of AA low producer genotype of IL-10 (P<.001). Both bipolar I and bipolar II patients not carrying guanine (G) high producer IL-6 allele showed a lower mean age at onset (P=.048). CONCLUSION These data support the existence of a genetic profile related to pro-inflammatory cytokines in patients affected by mood disorders. The differences observed across the three clinical phenotypes suggest the presence of different pathogenetic mechanisms involved in the susceptibility of phenotypically different mood disorders.

Epigenetic regulation of fatty acid amide hydrolase in Alzheimer disease.

Objective Alzheimer disease (AD) is a progressive, degenerative and irreversible neurological disorder with few therapies available. In search for new potential targets, increasing evidence suggests a role for the endocannabinoid system (ECS) in the regulation of neurodegenerative processes. Methods We have studied the gene expression status and the epigenetic regulation of ECS components in peripheral blood mononuclear cells (PBMCs) of subjects with late-onset AD (LOAD) and age-matched controls (CT). Results We found an increase in fatty acid amide hydrolase (faah) gene expression in LOAD subjects (2.30±0.48) when compared to CT (1.00±0.14; *p<0.05) and no changes in the mRNA levels of any other gene of ECS elements. Consistently, we also observed in LOAD subjects an increase in FAAH protein levels (CT: 0.75±0.04; LOAD: 1.11±0.15; *p<0.05) and activity (pmol/min per mg protein CT: 103.80±8.73; LOAD: 125.10±4.00; *p<0.05), as well as a reduction in DNA methylation at faah gene promoter (CT: 55.90±4.60%; LOAD: 41.20±4.90%; *p<0.05). Conclusions Present findings suggest the involvement of FAAH in the pathogenesis of AD, highlighting the importance of epigenetic mechanisms in enzyme regulation; they also point to FAAH as a new potential biomarker for AD in easily accessible peripheral cells.

The C9ORF72 hexanucleotide repeat expansion is a rare cause of schizophrenia

A hexanucleotide repeat expansions in the first intron of C9ORF72 has been shown to be responsible for a high number of familial cases of amyotrophic lateral sclerosis and/or frontotemporal lobar degeneration. The same mutation has been described in a patient with bipolar disorder, but up to now, not in patients suffering from schizophrenia. We determined the frequency of the C9ORF72 hexanucleotide repeat expansions in a population of 298 patients with schizophrenia or schizoaffective disorder. The pathogenic repeat expansion was detected in 2 patients (0.67%). Both of them presented with auditory hallucinations and had comorbid alcohol abuse. In addition, a positive family history for psychiatric and/or neurodegenerative diseases was present. The repeat expansion in the C9ORF72 gene is a rare, but possible, cause of schizophrenic spectrum disorders. We cannot rule out however whether the number of repeats influence the phenotype.