B. Benatti

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.

Mood stabilizers for patients with bipolar disorder: the state of the art

Bipolar disorder (BD) is a prevalent and disabling condition, often comorbid with other medical and psychiatric conditions and frequently misdiagnosed. International treatment guidelines for BD recommend the use of mood stabilizers – either in monotherapy or in association – as the gold standard in both acute and long-term therapy. Commonly used in the clinical practice of BD, mood stabilizers have represented an evolving field over the last few years. The concept of stabilization, in fact, has been stressed as the ultimate objective of the treatment of BD, given the chronic and recurrent nature of the illness, which accounts for its significant levels of impairment and disability. To date, different compounds are included within the broad class of mood stabilizers, with lithium, anticonvulsants and, more recently, atypical antipsychotics being the most representative agents. This article is aimed at providing an updated review of the available literature in relation to the role of mood stabilizers in BD, with particular emphasis on their mechanism of action, main clinical aspects and specific use in the different phases of BD treatment, according to the most recently published international treatment guidelines.

Characterizing impulsivity profile in patients with obsessive-compulsive disorder

Abstract Objective. Impulsivity represents a key dimension in obsessive–compulsive disorder (OCD), in relation to outcome and course. It can be assessed through the Barratt Impulsiveness Scale (BIS), which explores three main areas: attentional, motor, and nonplanning. Present study was aimed to assess level of impulsivity in a sample of OCD patients, in comparison with healthy controls, using the BIS. Methods. Seventy-five OCD outpatients, 48 of them having psychiatric comorbidities and 70 healthy controls, were assessed through the BIS, and their scores were analyzed using Students t-test for independent samples, on the basis of demographic and clinical characteristics. Results. BIS total scores were significantly higher (P: 0.01) in patients compared to controls, with no difference between pure and comorbid patients. Attentional impulsivity scores were significantly higher than controls in patients with pure (P < 0.001) and comorbid OCD (P < 0.001), without differences among them. Patients with multiple OC phenotypes showed higher, though statistically non significant, total and attentional scores, compared to single phenotype patients. In addition, patients with comorbid major depressive disorder had higher, though statistically non significant, total and attentional scores, compared to patients with comorbid bipolar disorder, generalized anxiety disorder, and other disorders. Conclusions. Present findings showed higher impulsivity levels in OCD patients versus controls, particularly in the attentional area, and ultimately suggest a potential cognitive implication.

Differences in latency to first pharmacological treatment (duration of untreated illness) in anxiety disorders: a study on patients with panic disorder, generalized anxiety disorder and obsessive–compulsive disorder

The latency to first pharmacological treatment (duration of untreated illness or ‘DUI’) is supposed to play a major role in terms of outcome in psychotic conditions. Interest in the field of affective disorders and, in particular, of duration of untreated anxiety, has been recently registered as well. However, a preliminary epidemiologic investigation of the phenomenon is necessary. The present study was aimed to investigate and compare age at onset, age at first pharmacological treatment and DUI in a sample of patients affected by different anxiety disorders. DUI was defined as the interval between the onset of the specific anxiety disorder and the administration of the first adequate pharmacological treatment in compliant subjects.

Augmentative transcranial direct current stimulation (tDCS) in poor responder depressed patients: a follow-up study.

OBJECTIVES Transcranial direct current stimulation (tDCS) is a non-invasive neurostimulation technique that has received increasing interest in the area of mood disorders over the last several years. While acute, double-blind, sham-controlled studies have already reported positive findings in terms of efficacy and safety for tDCS, follow-up data are lacking. This need prompted the present follow-up study, which assesses post-acute effects of tDCS (no maintenance stimulation was performed), in the mid-term, in a sample of major depressives. METHODS After completing an acute, open trial of tDCS, 23 outpatients with either major depressive disorder or bipolar disorder entered a naturalistic follow-up (T1) with clinical evaluations at one week (T2), 1 month (T3), and 3 months (T4). A quantitative analysis of Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), and Young Mania Rating Scale (YMRS) total scores, through repeated measures analysis of variance (ANOVA) (T1-T4) and paired t-test for comparing specific time points (T1-T2, T2-T3, and T3-T4), was performed. In addition, a qualitative analysis on the basis of treatment response and remission (HAM-D) was performed. RESULTS Even though a progressive reduction of follow-up completers was observed from T2 to T4 (95.6% at T2, 65.2% at T3, and 47.8% at T4), the antidepressant effects of acute tDCS persisted over 3 months in almost half of the sample. Of note, no post-acute side effects emerged during the follow-up observation. The most frequent causes of drop-out from this study included major modifications in therapeutic regimen (30%) and poor adherence to follow-up visits (17%). CONCLUSIONS In this mid-term, open, follow-up study, tDCS showed mixed results. Further controlled studies are urgently needed to assess its effects beyond the acute phase.

Childhood, adolescent and adult age at onset and related clinical correlates in obsessive–compulsive disorder: a report from the International College of Obsessive–Compulsive Spectrum Disorders (ICOCS)

Abstract Objective: Many studies suggest that age at onset (AAO) is an important factor for clinically differentiating patients with juvenile and adult onset of obsessive–compulsive disorder (OCD). The present international study aimed to assess the prevalence of different AAO groups and compare related socio-demographic and clinical features in a large sample of OCD patients. Methods: A total of 431 OCD outpatients, participating in the ICOCS network, were first categorised in groups with childhood (≤12 years), adolescent (13–17 years) and adult-onset (≥18 years), then in pre-adult and adult onset (≥18 years) and their socio-demographic and clinical features compared. Results: Twenty-one percent (n = 92) of the sample reported childhood onset, 36% (n = 155) adolescent onset, and 43% (n = 184) adult onset. Patients with adult onset showed a significantly higher proportion of females compared with the other subgroups (χ2 = 10.9, p< 0.05). Childhood- and adolescent-onset patients had been more frequently treated with cognitive behavioural therapy (CBT), compared to adult-onset patients (χ2 = 11.5; p < 0.05). The pre-adult- versus adult-onset analysis did not show any additional significant difference. Conclusions: The present international multicentre study confirms that OCD onset occurs more frequently before adult age, with approximately one out of five patients showing childhood onset. Pre-adult onset was associated with higher rate of CBT, while adult onset was more prevalent in females.

Factors characterizing access and latency to first pharmacological treatment in Italian patients with schizophrenia, mood, and anxiety spectrum disorders

Latency to first pharmacological treatment [duration of untreated illness (DUI)] in psychiatric disorders can be measured in years, with differences across diagnostic areas and relevant consequences in terms of socio-occupational functioning and outcome. Within the psychopathological onset of a specific disorder, many factors influence access and latency to first pharmacotherapy and the present study aimed to investigate such factors, through an ad-hoc developed questionnaire, in a sample of 538 patients with diagnoses of schizophrenia-spectrum disorder (SZ), mood disorder (MD), and anxiety disorder (AD). Patients with SZs showed earlier ages at onset, first diagnosis and treatment, as well as shorter DUI compared with other patients (43.17 months vs. 58.64 and 80.43 months in MD and AD; F=3.813, P=0.02). Patients with MD and AD reported more frequently onset-related stressful events, benzodiazepines as first treatment, and autonomous help seeking compared with patients with SZs. In terms of first therapist, psychiatrist referral accounted for 43.6% of the cases, progressively decreasing from SZ to MD and AD (57.6, 41.8, and 38.3%, respectively). The opposite phenomenon was observed for nonpsychiatrist clinician referrals, whereas psychologist referrals remained constant. The present findings confirm the presence of a relevant DUI in a large sample of Italian patients with different psychiatric disorders (5 years, on average), pointing out specific differences, in terms of treatment access and latency, between psychotic and affective patients. Such aspects are relevant for detection of at-risk patients and implement early intervention programs.

Parsing the phenotype of obsessive-compulsive tic disorder (OCTD): a multidisciplinary consensus

Abstract Obsessive-Compulsive Disorder (OCD) and Tic Disorder (TD) are highly disabling and often comorbid conditions. Of note, the DSM-5 acknowledged a new ‘tic-related’ specifier for OCD, which might be referred to as Obsessive-Compulsive Tic Disorder (OCTD), raising new interest toward a better clinical characterisation of affected patients. Available literature indicates that early onset, male gender, sensory phenomena and obsessions of symmetry, aggressiveness, hoarding, exactness and sounds as well as comorbidity with Attention Deficit Hyperactivity Disorder (ADHD) may be of more frequent observation in patients with OCTD. In order to share expertise in the field from different perspectives, a multidisciplinary panel of Italian clinicians, specifically involved in the clinical care of OCD and TD patients, participated into a consensus initiative, aimed to produce a shared document. As a result, after having examined the most relevant literature, authors sought to critically identify and discuss main epidemiologic, socio-demographic and clinical features characterising OCTD patients, along with other specific aspects including Health-Related Quality-of-Life (HRQoL), economic consequences related with the condition and its management, as well as treatment-related issues, that need to be further investigated.

Efficacy, tolerability, compliance, and quality of life of patients with mood disorders switched from Quetiapine immediate release to extended release

The present study aimed to assess switch from immediate-release (IR) to extended-release (XR) Quetiapine in terms of efficacy, tolerability, compliance, and quality of life in a sample of patients with mood disorders. Thirty patients, 10 with major depressive disorder and 20 with bipolar disorder, with residual depressive symptoms, who had switched from Quetiapine IR (mean 365 mg/day) to XR (mean 373 mg/day), were recruited and evaluated using different psychometric scales, administered at T0 (switch), T1, and T2 (1 and 6 weeks after the switch, respectively). A significant reduction from T0 to T2 of the total scores on the Hamilton Depression Rating Scale (t=2.15; P=0.04), Hamilton Anxiety Scale (t=3.04; P=0.006), and Clinical Global Impression-Severity Item (t=2.8; P=0.01) was found. No differences were found in terms of compliance and quality of life. The switch was well tolerated by 2/3 of patients. Most reported side effects were early/central insomnia with day drowsiness (16.7%), increased appetite and weight (8.4%), mild asthenia (4.2%), and constipation (4.2%), which, in two cases, led to switch interruption. Strategies to relieve side effects, including gradual cross-switch, improved switch feasibility. Switch from Quetiapine IR to XR seems to be associated with clinical improvement in major depressives with residual symptoms, although some patients may report side effects because of the different pharmacokinetics.