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Camilla Gesi,1 Silvia Paletta,2 Maria Carlotta Palazzo,1 Bernardo Dell’Osso,1,3 Claudio Mencacci,1 Giancarlo Cerveri2 1Department of Mental Health and Addiction, ASST FBF Sacco, Milan, Italy; 2Department of Mental Health and Addiction, ASST Lodi, Lodi, Italy; 3School of Medicine University of Milan, Milan, ItalyCorrespondence: Silvia Paletta Email silvia.paletta@asst-Lodi.itAbstract: Cariprazine is an antipsychotic medication which received approval from the US Food and Drug Administration for the treatment of schizophrenia in September 2015. Cariprazine is a dopamine D3 and D2 receptor partial agonist, with a preference for the D3 receptor. Furthermore, although to a more limited extent, cariprazine also exhibits partial agonism at the level of 5-HT1A receptors, thus exerting an antidepressant effect in addition to the antipsychotic effect. The most commonly encountered adverse events are extrapyramidal symptoms and akathisia. Short-term weight gain appears infrequently. Cariprazine is not associated with any clinically meaningful alterations in metabolic variables, prolactin, or ECG QT interval. Cariprazine is also approved for the acute treatment of manic or mixed episodes associated with bipolar I disorder. Clinical trials of cariprazine are ongoing in patients with acute bipolar I depression and as adjunctive treatment to antidepressant therapy in patients with major depressive disorder. In this article, we present some significant clinical cases regarding the use of cariprazine, with the hope that our experience can provide insight or suggestions to be used in clinical practice.Keywords: cariprazine, schizophrenia, bipolar disorder, effectiveness, tolerability

Tra gli antipsicotici cosiddetti "di terza generazione", dotati di agonismo parziale sui recettori D 2 , cariprazina è in particolare contraddistinta da agonismo parziale D 3 /D 2 con affinità particolarmente elevata per i recettori D 3 , oltre che da un'azione di antagonismo 5HT2B e 5TH2A e agonismo parziale 5TH1A. L'insieme di queste attività recettoriali conferisce a cariprazina un profilo di azione sia sui sintomi positivi sia su quelli negativi, offrendo nuove opportunità di trattamento per disturbi dello spettro schizofrenico. In particolare, cariprazina potrebbe rappresentare una valida alternativa per pazienti che presentano sintomi negativi e cognitivi prominenti e che presentano una risposta sub-ottimale ad altre molecole antipsicotiche. L'obiettivo di questa rassegna è quello di presentare alcuni casi clinici in cui la risposta parziale o sub-ottimale a un precedente trattamento antipsicotico ha suggerito l'opportunità di uno switch a cariprazina, nonché di illustrare le modalità e l'esito dello switch. La discussione dei casi clinici vuole fornire alcune informazioni utili per l'utilizzo di cariprazina nella pratica clinica quotidiana.

Introduction:Obsessive-compulsive disorder (OCD) is a highly disabling condition, with frequent early onset. Adult/adolescent OCD has been extensively investigated, but little is known about prevalence and clinical characterization of geriatric patients with OCD (G-OCD = 65 years). The present study aimed to assess prevalence of G-OCD and associated socio-demographic and clinical correlates in a large international sample.Methods:Data from 416 outpatients, participating in the ICOCS network, were assessed and categorized into 2 groups, age < vs = 65 years, and then divided on the basis of the median age of the sample (age < vs = 42 years). Socio-demographic and clinical variables were compared between groups (Pearson Chi-squared andttests).Results:G-OCD compared with younger patients represented a significant minority of the sample (6% vs 94%,P< .001), showing a significantly later age at onset (29.4 ± 15.1 vs 18.7 ± 9.2 years,P< .001), a more frequent adult onset (75% vs 41.1%,P< .001) and a less frequent use of cognitive-behavioural therapy (CBT) (20.8% vs 41.8%,P< .05). Female gender was more represented in G-OCD patients, though not at a statistically significant level (75% vs 56.4%,P= .07). When the whole sample was divided on the basis of the median age, previous results were confirmed for older patients, including a significantly higher presence of women (52.1% vs 63.1%,P< .05).Conclusions:G-OCD compared with younger patients represented a small minority of the sample and showed later age at onset, more frequent adult onset and lower CBT use. Age at onset may influence course and overall management of OCD, with additional investigation needed.

Objectives: Cognitive impairment may affect patients with Bipolar Disorder (BD) beyond the acute episodes, qualifying as a potential endophenotype. However, which cognitive domains are specifically affected in euthymic patients with BD and the potential influence of confounding factors (e.g., age and concomitant pharmacological treatment) are still a matter of debate. The present study was, therefore, conducted to assess cognitive performance across specific domains in euthymic bipolar patients, not older than 50 years (to avoid potential age-related bias) versus healthy controls (HCs). Methods: A cognitive task battery, including the Wisconsin Card Test, Span Attention Test, Tower of London, Trail Making Test, Verbal Fluency Test, Matrices Scores and N-Back, was administered to 62 subjects (30 bipolar patients and 32 matched HCs) and differences between the groups analyzed. Results: Bipolar patients performed significantly worse than HCs in the Span Forward task, in the expression of Verbal Fluency Test (Category) and in the N-Back task (all p Conclusion: The present study pointed out significant differences in terms of cognitive performance between euthymic bipolar patients and HCs, supporting the notion that specific cognitive functions may remain impaired even after the resolution of the acute episodes in subjects suffering from BD. Future studies on larger samples are warranted to confirm the present results and further explore potential differences in cognitive impairment across specific bipolar subtypes.

Anxiety disorders are common, comorbid, and disabling conditions, often underdiagnosed and under-treated, typically with an early onset, chronic course, and prolonged duration of untreated illness. The present study aimed to explore the influence of sociodemographic and clinical factors in relation to onset and latency to treatment in patients with generalized anxiety disorder (GAD), panic disorder (PD), and obsessive-compulsive disorder (OCD). A total of 157 patients with a Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Text Revision (DSM-IVTR) diagnosis of PD (n=49), GAD (n=68), and OCD (n=40) were recruited, and epidemiological and clinical variables were collected through a specific questionnaire. Statistical analyses were carried out to compare variables across diagnostic groups. PD, GAD, and OCD patients showed a duration of untreated illness of 53.9 ±81.5, 77.47 ±95.76, and 90.6± 112.1 months, respectively. Significant differences between groups were found with respect to age, age of first diagnosis, age of first treatment, family history of psychiatric illness, onset-related stressful events, benzodiazepine prescription as first treatment, antidepressant prescription as first treatment, and helpseeking (self-initiated vs. initiated by others). Patients with GAD, PD, and OCD showed significant differences in factors influencing onset and latency to treatment, which may, in turn, affect condition-related outcome and overall prognosis. Further studies with larger samples are warranted in the field.

Background 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. Methods 101 SKZ or SSD patients were assessed with respect to DUI and related variables through clinical interview and questionnaire. Results Patients with SKZ showed earlier ages of onset, first diagnosis and first antipsychotic treatment compared with patients with other SSDs (F = 11.02, p

OBJECTIVE In patients with affective disorders, benzodiazepines (BZDs) are frequently administered at the onset, sometimes inappropriately. We sought to identify clinical variables associated with first BZD prescription in a large sample of patients with affective disorders. METHODS Four hundred sixty patients with mood or anxiety disorders attending different psychiatric services were assessed comparing those who received BZD as first treatment (BZD w/) and those who did not (BZD w/o). RESULTS More than one third (35.7%) of the total sample had received BZDs as first prescription. In relation to mood disorders, BZD w/ subjects more frequently (a) had not a psychiatrist as first therapist, (b) had anxious symptoms at onset, (c) had adjustment disorder as first diagnosis, (d) were treated as outpatients. In relation to specific diagnoses, (a) personal decision of treatment for major depressive disorder, (b) outpatient status for bipolar disorder and (c) longer duration of untreated illness for adjustment disorder were more frequently associated with first BZD prescription. For anxiety disorders, the presence of stressful life events and the diagnoses of panic disorder or specific phobias were more frequently observed in BZD w/ patients. CONCLUSION Patients with affective disorders frequently received BZDs as first prescription with significant differences between and within mood and anxiety disorders.

Background Working memory (WM) deficits are among the most frequently impaired cognitive domains in patients with Bipolar Disorder (BD), being considered promising cognitive endophenotype of the disorder. However, the related neurobiological correlates still deserve further investigation. The present study was aimed to explore whether dorsolateral prefrontal cortex (DLPFC) activity during WM processing was abnormal in euthymic bipolar patients and may represent a potential trait-related phenotype associated with the disorder. Methods Using 3 Tesla functional Magnetic Resonance Imaging (3T fMRI), we studied 28 euthymic bipolar patients (15 BDI and 13 BDII), and 27 healthy controls (HCs), matched for a series of socio-demographic variables, while performing the N-back task for WM assessment. Results We found that euthymic bipolar patients showed increased right middle frontal gyrus engagement compared with HCs (FWE-corrected p=1×10−3), regardless of WM load, and in spite of similar WM behavioral performance between groups. In particular, BDI patients had greater BOLD signal change compared to HCs (post-hoc Tukey HSD, p=1×10−3), while BDII patients expressed an intermediate pattern of activation between BDI patients and HCs. No other significant effects were detected in the corrected whole-brain analysis. Limitations Sample size, cross-sectional assessment and potential influence of some clinical variables. Conclusions Results provide direct evidence of a primary physiological abnormality in DLPFC function in BDI and II, even in the absence of behavioral differences with HCs. Such exaggerated fMRI response suggests inefficient WM processing in prefrontal circuitry, and further studies are warranted to investigate whether the dysfunction is related to the genetic risk for the disorder.

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.

ObjectiveObsessive-compulsive disorder (OCD) is associated with variable risk of suicide and prevalence of suicide attempt (SA). The present study aimed to assess the prevalence of SA and associated sociodemographic and clinical features in a large international sample of OCD patients.MethodsA total of 425 OCD outpatients, recruited through the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS) network, were assessed and categorized in groups with or without a history of SA, and their sociodemographic and clinical features compared through Pearson’s chi-squared and t tests. Logistic regression was performed to assess the impact of the collected data on the SA variable.Results14.6% of our sample reported at least one SA during their lifetime. Patients with an SA had significantly higher rates of comorbid psychiatric disorders (60 vs. 17%, ppp2=11.4, pConclusionsOur international study found a history of SA prevalence of ~15% in OCD patients, with higher rates of psychiatric and medical comorbidities and previous hospitalizations in patients with a previous SA. Along with potential geographical influences, the presence of the abovementioned features should recommend additional caution in the assessment of suicide risk in OCD patients.

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.

OBJECTIVE: 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. METHODS: A computerized literature search of the published literature on mental health literacy was undertaken, focusing on the question of whether increased mental health literacy led to increased treatment-seeking and pharmacotherapy adherence in individuals with anxiety disorders. RESULTS: Twelve relevant articles were identified. All reported that improving mental health literacy leads to raised awareness, and in 10 out of 12 studies, increased help-seeking. However, there is currently no unequivocal evidence to show that increasing health literacy leads to increased use of medication in any psychiatric disorder, including anxiety disorders. Two studies show that knowledge of presumed biological mechanisms can predict use of psychotropic medication, including antidepressants, in psychiatric disorders, however, not specifically in anxiety disorders. CONCLUSION: There have been few investigations of health literacy focused on psychotropic medications. Given the prevalence, burden and sub-optimal recognition, and treatment of anxiety disorders, further work is needed to determine whether increased mental health literacy is associated with treatment-seeking and medication adherence in patients with these disorders.

Introduction Obsessive compulsive disorder (OCD) is a chronic and disabling condition, often showing an early onset (1). OCD has been extensively studied in adults, adolescents, and children, but a critial gap remains in the clinical characterization of older patients (2). The present study was aimed to assess prevalence of geriatric OCD (G-OCD ≥ 65 years) and associated sociodemographic and clinical correlates of geriatric OCD in a large international sample of OCD patients. Methods Data of 416 outpatients recruited by different OCD Clinics worldwide, participating in the International College of Obsessive-compulsive Spectrum Disorders (ICOCS) network (3), were assessed and first categorized into 2 groups, age Results Patients with G-OCD represented a significant minority of the overall sample (n=24, 6% of the total sample vs age When the whole sample was divided on the basis of the median age (age Conclusions The present international multicenter study revealed a significantly lower rate of patients with age ≥ 65 years compared to patients younger than 65 years. Patients with G-OCD showed a significantly higher age at onset and rate of adult onset compared to non-geriatric patients. Moreover, in G-OCD patients CBT was less frequently utilized. Subgroups divided on the basis of the median age of the sample showed that the age ≥ 42 years group had a significantly later onset of illness and higher rate of adult onset and female gender.

Mutations in progranulin gene (GRN) are the most common cause of autosomal dominant familial frontotemporal lobar degeneration (FTLD). In addition, GRN variability influences the risk to develop the disease in non-carriers (sporadic FTLD). We evaluated progranulin gene (GRN) promoter methylation levels in peripheral blood mononuclear cells isolated from 38 patients with sporadic FTLD compared with 38 controls, and correlate them with GRN mRNA expression rate. The percentage of methylation of the GRN promoter was increased in patients with FTLD compared with controls (61.5 vs. 46.3 %, P0.001). A trend towards decreased GRN relative expression was observed in patients compared with controls (threefold decrease over controls, P0.05), together with a negative correlation between the degree of GRN promoter methylation and mRNA GRN levels (ρ = -0.1, P0.05). GRN promoter methylation was not correlated with age. In conclusion, the degree of methylation of the GRN promoter is increased in patients with FTLD as compared with controls, likely leading to a decreased expression of GRN.

Obsessive compulsive disorder (OCD) showed a lower prevalence of cigarette smoking compared to other psychiatric disorders in previous and recent reports. We assessed the prevalence and clinical correlates of the phenomenon in an international sample of 504 OCD patients recruited through the International College of Obsessive Compulsive Spectrum Disorders (ICOCS) network.Cigarette smoking showed a cross-sectional prevalence of 24.4% in the sample, with significant differences across countries. Females were more represented among smoking patients (16% vs 7%; pWe found a lower cross-sectional prevalence of smoking among OCD patients compared to findings from previous studies in patients with other psychiatric disorders but higher compared to previous and more recent OCD studies. Geographic differences were found and smoking was more common in females and comorbid Tourette’s syndrome/tic disorder.

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.101 SKZ or SSD patients were assessed with respect to DUI and related variables through clinical interview and questionnaire.Patients with SKZ showed earlier ages of onset, first diagnosis and first antipsychotic treatment compared with patients with other SSDs (F = 11.02, p0.001; F = 12.68, p0.001; F = 13.74, p0.001, respectively) who showed an earlier access to benzodiazepines than SKZ patients (F = 6.547; p0.05). Dividing the total sample by the epoch of onset (before 1978; between 1978-2000; after 2000) showed a significantly later age of onset in patients with onset within the two most recent epochs (F = 7.46; p0.001) and a reduced DUI across epochs (from 144 to 41 to 20 months, on average; F = 11.78, p0.001).Schizophrenic patients showed earlier onset and longer DUI compared with patients with other SSDs. Data on the total sample showed a later age of onset and a reduced DUI across epochs.

Generalized anxiety disorder (GAD) and panic disorder (PD) are disabling conditions, often comorbid with other anxiety disorders. The present study was aimed to assess prevalence and related disability of comorbid social phobia (SP) and obsessive-compulsive disorder (OCD) in 115 patients with GAD (57) or PD (58).Patients were classified as having threshold, subthreshold, or no comorbidity, and related prevalence rates, as well as disability (Sheehan Disability Scale, SDS), were compared across diagnostic subgroups.SP and OCD comorbidities were present in 30.4% of the sample, with subthreshold comorbidities present at twice the rate of threshold ones (22.6% vs. 11.3%). Compared with GAD patients, PD patients showed significantly higher subthreshold and threshold comorbidity rates (27.6% and 13.8% vs. 17.5% and 8.8%, respectively). Comorbid PD patients had higher SDS scores than the comorbid and non-comorbid GAD subjects. The presence of threshold SP comorbidity was associated with the highest SDS scores.SP and OCD comorbidities were found to be prevalent and disabling among GAD and PD patients, with higher subthreshold than threshold rates, and a negative impact on quality of life. Present findings stress the importance of a dimensional approach to anxiety disorders, the presence of threshold and subthreshold comorbidity being the rule rather than the exception.

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).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.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.

Bipolar disorder (BD) is a chronic and disabling mood disorder, with significant suicide rates among psychiatric disorders. Although the pathophysiological bases of BD have not been fully elucidated yet, over the last two decades, neuroimaging research has documented specific neuroanatomic and functional abnormalities in bipolar patients. The present review was aimed to provide an updated and comprehensive overview about currently available evidence on main structural and functional alterations documented in BD by neuroimaging procedures, through a Medline research. Among the structural alterations, the most consistent ones seem to be at the level of frontal, temporal and insular cortices, amygdala and basal ganglia, having been ventriculomegaly reported as well. Magnetic resonance spectroscopy findings showed, in turn, biochemical alterations in several neurotransmitter systems. Functional neuroimaging data are quite heterogeneous with positron emission tomography and single photon emission computed tomography studies showing phase-specific abnormalities of blood flow and glucose metabolism, as well as modifications of serotonin transporter density and binding. Functional magnetic resonance imaging data documented impaired neural networks involved in emotional regulation, including anterior limbic, ventral and dorsal prefrontal regions. Taken as a whole, neuroimaging data are strongly advancing the understanding of the neural bases of BD as described in the present review.

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

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. © 2014 Elsevier Inc.

Objective Recent data have shown that genetic variability in the progranulin (GRN) gene may contribute to the susceptibility to developing bipolar disorder (BD). However, in regard to patients with BD, no information is available on the role of genetic variability and plasma progranulin levels in different types of this disorder. Methods In this study, we performed an association analysis of GRN in an Italian population consisting of 134 patients with BD and 232 controls to evaluate progranulin plasma levels. Results The presence of the polymorphic variant of the rs5848 single nucleotide polymorphism is protective for the development of bipolar I disorder (BD-I) (odds ratio = 0.55, 95% confidence interval: 0.33–0.93; p = 0.024) but not bipolar II disorder (BD-II) (p > 0.05). In addition, plasma progranulin levels are significantly decreased in BD [mean ± standard deviation (SD) 112 ± 35 versus 183 ± 93 ng/mL in controls; p

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.A computerized literature search of the published literature on mental health literacy was undertaken, focusing on the question of whether increased mental health literacy led to increased treatment-seeking and pharmacotherapy adherence in individuals with anxiety disorders.Twelve relevant articles were identified. All reported that improving mental health literacy leads to raised awareness, and in 10 out of 12 studies, increased help-seeking. However, there is currently no unequivocal evidence to show that increasing health literacy leads to increased use of medication in any psychiatric disorder, including anxiety disorders. Two studies show that knowledge of presumed biological mechanisms can predict use of psychotropic medication, including antidepressants, in psychiatric disorders, however, not specifically in anxiety disorders.There have been few investigations of health literacy focused on psychotropic medications. Given the prevalence, burden and sub-optimal recognition, and treatment of anxiety disorders, further work is needed to determine whether increased mental health literacy is associated with treatment-seeking and medication adherence in patients with these disorders. Copyright © 2014 John WileySons, Ltd.

SummaryBackground 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±42.6 vs 75.8±105.2 months, P

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.

Peg-interferon (Peg-IFN) and ribavirin (RBV) therapy is reported to induce psychiatric symptoms and syndromes in 20% of patients treated for Hepatitis C Virus (HCV) infection. Present study was aimed to quantify the phenomenon and assess the influence of psychiatric counseling over antiviral completion rate and the use of psychometric tools, in terms of prediction of psychopathological outcome. Ninety-six HCV patients were assessed, before antiviral treatment, by means of the Sheehan Disability Scale (SDS), Mood Disorder Questionnaire (MDQ), Symptom Checklist-90, and Internal State Scale (ISS). Sociodemographic and clinical variables and completion rate were collected. Binary logistic regression was performed to evaluate whether scores were predictive of psychiatric visit, development of psychiatric disorders, and need for treatment. Ninety-five patients (99%) completed antiviral treatment; 27 subjects (29%) needed psychiatric visit: among them, mood disorder was diagnosed in 15 (16%) and were pharmacologically treated. Baseline SDS and MDQ higher scores were found to be predictive of psychiatric visit [odds ratio (OR)=1.258, P0.001 and OR=1.425, P=0.05, respectively]. Furthermore, higher MDQ score (P=0.017) and ISS hostility scores (OR=1.048, P=0.014) at baseline predicted the subsequent development of mood episodes, while ISS activation correlated negatively (OR=0.948, P=0.009). Finally, the need for treatment was predicted by higher scores at the MDQ and ISS activation items (OR=2.467, P=0.030; OR=0.970, P=0.038). Present findings suggest that psychiatric counseling may be needed in almost 30% of HCV patients on antiviral treatment, with positive influence over the completion rate. Baseline higher scores at psychometric questionnaires-MDQ-in particular, predictors of psychopathological outcome during Peg-IFN and RBV therapy in patients with chronic HCV-correlated hepatitis reflecting individual functioning before starting antiviral therapy and positive history for mood disorders, seem to predict psychiatric visit, onset of mood episodes, and need for psychopharmacological treatment. Further investigation is warranted to confirm results.

BD is a prevalent mood disorder, often comorbid with other medical and psychiatric conditions and frequently misdiagnosed (Altamura et al., 2011a). Intense emotional states that occur in BD comprise manic, hypomanic, mixed or depressive episodes. According to the Diagnostic and Statistical Manual of Mental Disorders, IVth edition, text revision (DSMIV–TR; American Psychiatric Association, 2000), BD spectrum ranges from cyclothymia to Bipolar I, Bipolar II Disorder and Not Otherwise Specified (NOS) forms. BD can also be conceptualized as a gradual change in mood scale, which ranges from severe depression to severe mania with an intermediate euthymic state or balanced mood. Dysthymia is a chronic state of mild low mood occurring for a minimum of two years. At the other end of the scale there is hypomania and severe mania. An alternative and broader dimensional approach conceptualizes BD as a continuum, between unipolar depression, schizoaffective disorder (which is considered by some authors a subcategory of BD) and schizophrenia. This theory may be supported from a clinical point of view by the fact that, sometimes, during severe manic, mixed or depressive episodes, bipolar patients experience psychotic symptoms, such as hallucinations or delusions. It is also supported by the presence of morphometric alterations of frequent observation among major psychoses, such as enlarged ventricles and white matter volume reductions in the left and temporoparietal regions (Czobor et al., 2007). In BD, symptomatic states are frequently associated with poor working functioning and social impairment. Bipolar patients, moreover, have higher suicide rates than the general population and among the highest of psychiatric patients. In a recent study on factors predicting suicide in BD, white race, family history of suicide, and previous cocaine abuse were considered predictive of suicidal behaviour (Cassidy, 2011). Usually BD develops in early adulthood/late teens, with an age of onset ranging from 15 to 50 years (Cassano et al., 2006). 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. 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 (Altamura et al., 2011b). Beyond the

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

Even though noradrenaline has been recognized as one of the key neurotransmitters in the pathophysiology of major depression (MD), noradrenergic compounds have been less extensively utilized in clinical practice, compared to selective serotonin reuptake inhibitors (SSRIs). The development of the first selective noradrenergic reuptake inhibitor (NRI), Reboxetine, has not substantially changed the state of the art. In addition, Atomoxetine, a relatively pure NRI used for the treatment of ADHD, has shown mixed results when administered in augmentation to depressed subjects. Through a Medline search from 2000 to 2010, the present article provides an updated overview of the main pharmacological and clinical aspects of antidepressant classes that, partially or selectively, act on the noradrenergic systems. The noradrenergic action plays an important clinical effect in different antidepressant classes, as confirmed by the efficacy of dual action antidepressants such as the serotonin noradrenaline reuptake inhibitors (SNRIs), the noradrenergic and dopaminergic reuptake inhibitor (NDRI) Bupropion, and other compounds (e.g., Mianserin, Mirtazapine), which enhance the noradrenergic transmission. In addition, many tricyclics, such as Desipramine and Nortriptyline, have prevalent noradrenergic effect. Monoamine oxidase inhibitors (MAOIs), moreover, block the breakdown of serotonin, noradrenaline, dopamine and increase the availability of these monoamines. A novel class of antidepressants--the triple reuptake inhibitors--is under development to selectively act on serotonin, noradrenaline, and dopamine. Finally, the antidepressant effect of the atypical antipsychotic Quetiapine, indicated for the treatment of bipolar depression, is likely to be related to the noradrenergic action of its metabolite Norquetiapine. Even though a pure noradrenergic action might not be sufficient to obtain a full antidepressant effect, a pronoradrenergic action represents an important element for increasing the efficacy of mixed action antidepressants. In particular, the noradrenergic action seemed to be related to the motor activity, attention, and arousal.

Objective To investigate the role in bipolar disorder of the C9ORF72 hexanucleotide repeat expansion responsible for frontotemporal lobe dementia and amyotrophic lateral sclerosis. Methods Eighty-nine subjects from a previously described panel of individuals with bipolar disorder ascertained for genetic studies were screened to detect expansion of the C9ORF72 repeat. One two-generation family with bipolar disorder and an expanded repeat was characterized in depth using molecular diagnostics, imaging, histopathology, and neurological and neuropsychological evaluation. Results One proband, with the typical clinical presentation of bipolar disorder, carried an expanded C9ORF72 allele of heterogeneous length between 14 and 20 kilobases (kb) as assessed by Southern blot. The expanded allele was inherited from a parent with atypical, late onset clinical features of bipolar disorder, who subsequently progressed to frontotemporal lobe dementia. The expansion in peripheral blood of the parent ranged from 8.5 to 20 kb. Cultured lymphoblastoid cells from this parent exhibited a homogeneous expansion of only 8.5 kb. Conclusions The disease course in the two generations described here demonstrates that expansion of the C9ORF72 may be associated with a form of bipolar disorder that presents clinically with classic phenomenology and progression to neurodegenerative disease. The frequency in our bipolar disorder cohort was only 1%, indicating that C9ORF72 is not a major contributor to bipolar disorder. DNA from cultured cells may be biased towards shorter repeats and nonrepresentative of the endogenous C9ORF72 expansion.

Introduction The etiology of bipolar disorder (BD) is poorly understood, involving genetic, epigenetic mechanisms and environmental contributions. Aim Among the candidate genes associated with major psychoses, the present study investigated the degree of DNA methylation at brain-derived neurotrophic factor (BDNF) gene promoter in peripheral blood mononuclear cells (PBMCs) isolated from bipolar patients. Methods DNA was isolated from the blood of 94 BD patients (49 BD I and 45 BD II) and 52 controls and converted with sodium bisulfite. Real Time Methylation Specific PCR was performed to quantify promoter methylation. Results A significant BDNF gene expression down-regulation was observed in BD II 0.53 ± 0.11%; p Conclusions 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 patophysiology an treatment response of BD.

IntroductionThe etiology of bipolar disorder (BD) is still poorly understood and it has been proposed that altered expression of multiple mRNAs, affecting neurotransmission, in psychotic subjects may be due to epigenetic mechanisms (e.g., DNA methylation or histone modification).AimsThe present collaborative study was aimed to investigate, in subjects with BD, dysregulation of DNA methylation, in the brain-derived neurotrophic factor (BDNF), previously associated with psychosis and linked to epigenetic changes at promoter regions, and in the nociceptin gene (N/OFQ), a new proposed target in psychiatric disorders.MethodsDNA was isolated from blood of patients diagnosed with BD (either type I [n = 19] or II [n = 20]) according to DSM-IV criteria, and from healthy controls (n = 20) and, thereafter, bisulfite conversion was performed. Real-Time Methylation Specific PCR (MSP) was used for the quantification of the methylated promoters in all samples.ResultsA hypermethylation of BDNF promoter region was observed in BD II patients (but not in BD I) compared to controls (CONT: 19.0 ± 3.2%; BD I: 27.2 ± 4.0%; BD II: 36.3 ± 6.2% * P = 0.0167; ANOVA F = 3.464; P = 0.0384; Bonferroni’s post hoc test). No significant differences were found for DNA methylation of N/OFQ promoter.ConclusionsPresent preliminary findings suggest selective changes in DNA methylation of BDNF promoter in type II bipolar patients 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.