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The aims of this study were to establish the prevalence of moderate and severe psychomotor agitation in patients hospitalized for an active phase of schizophrenia, the associations between psychomotor agitation and patients' demographic and clinical variables, the intra-individual stability of the agitated/non-agitated dichotomy in independent psychotic breakdowns. The study was performed on a database relative to 630 inpatients hospitalized with a diagnosis of schizophrenia. Psychomotor agitation was measured with the Positive and Negative Syndrome Scale - Excited Component (PANSS-EC). Prevalence of moderate and severe psychomotor agitation was 40.5% and 23.7%, respectively. Non-agitated patients were older, with longer illness history and duration of untreated psychosis, were more frequently on antipsychotic medication, had lower incidence of recent use of substances, and functioned better before the index hospitalization than moderately and/or severely agitated patients. Non-agitated patients had lower scores for total PANSS and Emsley's positive and anxiety dimensions. Compared with the severely agitated group, non-agitated and moderately agitated patients scored more in Emsley's depression dimension. Poor functioning before index hospital admission, higher scores for negative subscale and Emsley's positive dimension and use of substances exerted an effect on risk of psychomotor agitation.

The purpose of the present study was to detect demographic and clinical factors associated with lifetime suicide attempts in Bipolar Disorder (BD). A total of 1673 bipolar patients from different psychiatric departments were compared according to the lifetime presence of suicide attempts on demographic/clinical variables. Owing to the large number of variables statistically related to the dependent variable (presence of suicide attempts) at the univariate analyses, preliminary multiple logistic regression analyses were realized. A final multivariable logistic regression was then performed, considering the presence of lifetime suicide attempts as the dependent variable and statistically significant demographic/clinical characteristics as independent variables. The final multivariable logistic regression analysis showed that an earlier age at first contact with psychiatric services (odds ratio [OR] = 0.97, p p p p p p

AIM The aim of the present study was to detect factors associated with duration of untreated illness (DUI) in bipolar disorder (BD). METHOD A total of 1575 patients were selected for the purposes of the study. Correlation analyses were performed to analyse the relation between DUI and quantitative variables. The length of DUI was compared between groups defined by qualitative variables through one-way analyses of variance or Kruskal-Wallis's tests according to the distribution of the variable. Linear multivariable regressions were used to find the most parsimonious set of variables independently associated with DUI: to this aim, qualitative variables were inserted with the numeric code of their classes by assuming a proportional effect moving from one class to another. RESULTS An inverse significant correlation between length of DUI and time between visits in euthymic patients was observed (r = -.52, P

Antipsychotic drugs are the preferred choice for schizophrenia treatment; however, response is highly variable. In the context of the search for predictors of antipsychotic treatment effectiveness, the evaluation of response within 2 weeks has been indicated to predict long-term outcome. Moreover, a focus on symptomatological domains could be helpful to better characterize antipsychotic response, identifying more specific predictors. Pharmacogenetic studies have indicated a role for rs6313 in the serotonin receptor gene HTR2A in affecting response to antipsychotics, with heterogeneous results. With the aim to test for the first time the application of a dimensional approach for the evaluation of early response, we carried out a genetic association study between rs6313 and antipsychotic response in two groups of schizophrenia patients in monotherapy with risperidone (n = 121) and olanzapine (n = 100). Patients were evaluated at the baseline and after 1 and 2 weeks of treatment. When comparing early responders versus early nonresponders, no association was detected for the two drugs separately, whereas by taking into consideration the two drugs together it was observed that carriers of the T allele had a higher response probability compared to noncarriers. Considering 2-week improvements, changes in PANSS total scores, subscores and in PANSS Emsley's symptomatological dimensions were associated with rs6313 for both risperidone and olanzapine. Moreover, the repeated measures analysis indicated an association of rs6313 with the disorganized thought dimension for risperidone, and with the depressive and anxiety dimensions for olanzapine. These data add support to the hypothesis that the HTR2A gene is involved in antipsychotic treatment outcome.

Borderline personality disorder (BPD) recognizes several psychopathological dimensions related to prefrontal cortex impairments. Transcranial Direct Current Stimulation (tDCS) targeting the right prefrontal dorsolateral cortex (DLPFC) positively influence cognitive functions related to impulsivity in healthy subjects. A randomized double-blind study was designed to investigate whether tDCS could modulate core dimensions (impulsivity, aggression, affective dysregulation) of BPD. Also effects on decision making process and substances craving was assessed. Patients were randomized to receive active-tDCS at 2 mA versus sham-tDCS, once a day for 15 sessions. Anode was placed on the right DLPFC (F4), cathode on the left DLPFC (F3). Impulsivity and aggression measures were significantly reduced only in patients treated with active-tDCS. Decision-making process was marginally influenced by the active current. Craving intensity was reduced only in the active-tDCS sample. Both groups showed improvements in the affective dysregulation dimension and anxious and depressive symptoms. The application of bilateral tDCS targeting right DLPFC with anodal stimulation seems to improve core dimensions of BPD (mainly impulsivity and aggression) probably by restoring prefrontal activity. tDCS might be a potential tool for preventing self-harming behaviors.

Background and aims The primary objective of this study was to investigate the prevalence of at-risk gambling in a large, unselected sample of outpatients attending two community mental health centers, to estimate rates according to the main diagnosis, and to evaluate risk factors for gambling. Methods All patients attending the centers were evaluated with the Canadian Problem Gambling Index and the Mini International Neuropsychiatric Interview. Diagnoses were checked with the treating psychiatrists and after a chart review of the university hospital discharge diagnoses. Results The rate of at-risk gambling in 900 patients was 5.3%. In those who gambled over the last year, 10.1% were at-risk gamblers. The rates in the main diagnostic groups were: 4.7% schizophrenia and related disorders, 4.9% bipolar disorder, 5.6% unipolar depression, and 6.6% cluster B personality disorder. In 52.1% of the cases, at-risk gambling preceded the onset of a major psychiatric disorder. In a linear regression analysis, a family history of gambling disorder, psychiatric comorbidities, drug abuse/dependence, and tobacco smoking were significantly associated with at-risk gambling. Discussion and conclusion The results of this study evidenced a higher rate of at-risk gambling compared to community estimates and call for a careful screening for gambling in the general psychiatric population.

Poor adherence to treatment remains a major problem in the management of patients with schizophrenia. In the 60s, first generation antipsychotics in depot formulation have been introduced on the market with the aim to improve adherence to therapy. However, the limited effectiveness on negative symptoms and the tendency to induce extrapyramidal side effects has limited their use. Currently there are five second-generation antipsychotic long-acting formulations and the use of these drugs has definitely changed perspective: they are no more restricted as compounds intended to improve compliance, but they can be considered first-line drugs with proven efficacy and good tolerability. In this narrative review the efficacy and tolerability of paliperidone palmitate, as well as the economic impact of the use of this particular molecule, have been evaluated in the short- and long-term treatment of schizophrenia. Taking into account the results of different studies, paliperidone, especially in his long-acting formulation, can be considered a viable and effective treatment for patients with schizophrenia, both in the short- and in the long term.

Paliperidone is a second-generation antipsychotic drug belonging to the class of benzisoxasole derivatives. Paliperidone is the major active metabolite of risperidone (9-OH-risperidone) and, as such, is comparable to the latter in terms of pharmacodynamic properties. However, due to its peculiar characteristics, paliperidone may be particularly useful in the treatment of schizophrenic patients. In this critical review of the literature the efficacy and tolerability in the short- and in the long-term have been evaluated in patients with schizophrenia. Taking into account the tolerability and efficacy data, together with the use of innovative sustained-release formulation, with a peculiar pharmacokinetic profile that allows single daily administration, paliperidone can be considered a valid option both for the short and the long-term treatment of schizophrenia.

Objective: ADHD remains a largely underdiagnosed disorder in Europe and especially in Italy. Aims of the present study were to assess the prevalence of ADHD and its clinical and demographic correlates in a large sample of Italian outpatients. Method: 634 outpatients accessing psychiatric services were assessed with the Mini-International Neuropsychiatric Interview (MINI) Plus V. 5.0.0 interview and the Adult ADHD self-report Scale Symptoms Checklist (ASRS)-V 1.1 Short Form. Patients positive to the ASRS-V 1.1 were assessed with the Diagnostic Interview for ADHD in Adults (DIVA) 2.0. Results: Of the total patients’ sample, 81 (12.8%) were positive on the ASRS-V 1.1. After performing the DIVA 2.0, 44 patients (6.9%) met the criteria for Adult ADHD. Significant clinical and demographic differences between ADHD positive and negative groups were found. Conclusion: The prevalence and correlates of ADHD comorbidity in our outpatient psychiatric population were comparable to those found in other high-income countries. Considering the prevalence of ADHD and its impact on functioning, implementing specific knowledge on this subject is needed.

BACKGROUND: Deficits in cortical gray matter (GM) have been found in patients with schizophrenia, with evidence of progression over time. The aim of this study was to determine the role of potential moderators of such changes, in particular of the amount and type of antipsychotic medication intake. METHODS: Longitudinal magnetic resonance imaging studies comparing changes in the volume of cortical GM over time between patients with schizophrenia and healthy control subjects published between January 1, 1983, and March 31, 2014, were analyzed. Hedges’ g was calculated for each study and volume changes from baseline to follow-up were analyzed. Meta-regression statistics were applied to investigate the role of potential moderators of the effect sizes. RESULTS: Eighteen studies involving 1155 patients with schizophrenia and 911 healthy control subjects were included. Over time, patients with schizophrenia showed a significantly higher loss of total cortical GM volume. This was related to cumulative antipsychotic intake during the interval between scans in the whole study sample. Subgroup meta-analyses of studies on patients treated with second-generation antipsychotics and first-generation antipsychotics revealed a different and contrasting moderating role of medication intake on cortical GM changes: more progressive GM loss correlated with higher mean daily antipsychotic intake in patients treated with at least one first-generation antipsychotic and less progressive GM loss with higher mean daily antipsychotic intake in patients treated only with second-generation antipsychotics. CONCLUSIONS: These findings add useful information to the controversial debate on the brain structural effects of antipsychotic medication and may have both clinical relevance and theoretical implications.

Objective: This study was designed to explore the efficacy and tolerability of oral paliperidone extended release (ER) in a sample of patients who were switched to flexible doses within the crucial first 5 years after receiving a diagnosis of schizophrenia. Methods: Patients were recruited from 23 countries. Adults with nonacute but symptomatic schizophrenia, previously unsuccessfully treated with other oral antipsychotics, were transitioned to paliperidone ER (3–12 mg/day) and prospectively treated for up to 6 months. The primary efficacy outcome for patients switching for the main reason of lack of efficacy with their previous antipsychotic was at least 20% improvement in Positive and Negative Syndrome Scale (PANSS) total scores. For patients switching for other main reasons, such as lack of tolerability, compliance or ‘other’, the primary outcome was non-inferiority in efficacy compared with the previous oral antipsychotic. Results: For patients switching for the main reason of lack of efficacy, 63.1% achieved an improvement of at least 20% in PANSS total scores from baseline to endpoint. For each reason for switching other than lack of efficacy, efficacy maintenance after switching to paliperidone ER was confirmed. Statistically significant improvement in patient functioning from baseline to endpoint, as assessed by the Personal and Social Performance scale, was observed ( p < 0.0001). Treatment satisfaction with prior antipsychotic treatment at baseline was rated ‘good’ to ‘very good’ by 16.8% of patients, and at endpoint by 66.0% of patients treated with paliperidone ER. Paliperidone ER was generally well tolerated, with frequently reported treatment-emergent adverse events being insomnia, anxiety and somnolence. Conclusions: Flexibly dosed paliperidone ER was associated with clinically relevant symptomatic and functional improvement in recently diagnosed patients with non-acute schizophrenia previously unsuccessfully treated with other oral antipsychotics.

Recent reviews of evidence-based guidelines for the clinical management of Bipolar Disorders (BD) have recommended that "all patients with BD be offered group or individual psychoeducation" to prevent relapse, improve treatment adherence, quality of life, and functioning. The present study evaluated the effectiveness of psychoeducation in routine mental health services in reducing number of hospitalisations and number of days spent in hospital, at a 1-year follow-up.A total of 102 outpatients were recruited from two Italian Departments of Mental Health. Inclusion criteria were a lifetime BD type I or II diagnosis, assessed with SCID, and ≥ 3 months of euthymia. Exclusion criteria were DSM-IV Axis I comorbidity, mental retardation (IQ70), organic brain damage, or deafness. All participants received standard psychiatric care, including standard pharmacological treatment; the experimental group also received 21 group psychoeducation sessions, weekly held and conducted according to Colom and Vieta's model.The number of patients hospitalised during the 1-year follow-up, the mean number of hospitalisations per patient, and the mean number of hospitalisation days were significantly lower for psychoeducated patients.Our findings support the view that group psychoeducation is an effective way to prevent hospitalisation and decrease hospital days in pharmacologically treated patients with bipolar disorder also in routine clinical settings. The results confirm that psychoeducation promotes improvement in illness course by preventing acute phases and enhancing mood stability, and consequently, improvement in the quality of life for people with BD.

The Schizophrenia Cognition Rating Scale (SCoRS), an interview-based assessment of cognition, has proved to be a valid measure of cognitive performance in patients with schizophrenia.The aims of this study were to analyze the validity of this scale in a naturalistic setting representative of the Italian system of psychiatric care, and to test whether the SCoRS could be appropriately used in different phases of illness and contexts of care.Eighty-six patients with schizophrenia (DSM-IV-TR criteria) (N = 59 clinically stabilized patients; N = 27 recently hospitalized patients) were administered the SCoRS. The reliability of SCoRS was assessed and global ratings were correlated with neurocognitive, clinical, and psychosocial functioning measures.SCoRS inter-rater and test-retest reliability were high. In clinically stabilized patients, SCoRS global ratings were significantly correlated with composite scores of cognitive performance (global cognitive index: r = -0.570, P0.001), symptoms (Positive and Negative Syndrome Scale (PANSS) total score: r = 0.602, P0.001), and psychosocial functioning (Global Assessment of Functioning (GAF): r = -0.532, P0.001; Health of the Nation Outcome Scale (HoNOS): r = 0.433, P0.001). On the other hand, no such correlations were found in recently hospitalized patients. Correlations with neuropsychological and functional measures were less significant as the severity of the patients' symptoms, especially positive symptoms, increased.The SCoRS is a valid measure of cognitive performance and is related to psychosocial functioning, especially in clinically stable patients with schizophrenia. The usefulness of the SCoRS in patients recently admitted to hospital for an acute phase of illness is uncertain.

Bipolar disorders (BDs) are prevalent, comorbid and disabling conditions, associated with the highest suicide risk among psychiatric illnesses. In the last few years, new efforts to better characterize the socio-demographic and clinical profiles of BD type I vs II have been documented by several reports, with novel and insightful findings in the field. The present multicenter study aimed to provide a comprehensive and reliable representation of the Italian reality, through the analysis of the largest national sample of bipolar patients collected so far. A total of 1500 patients (BD I n = 963 and BD II n = 537) from different psychiatric departments, participating in the Italian Chapter of the “International Society of Bipolar Disorders” (ISBD), were assessed and divided into two groups on the basis of their diagnostic subtype, and different socio-demographic and clinical variables were compared between the two subgroups. Chi-squared tests for categorical variables and t tests for continuous variables were performed for group comparison. Furthermore, a multivariable logistic regression was performed, considering diagnostic bipolar subtype (type I or II) as dependent variable, and socio-demographic/clinical characteristics as independent variables. BD I vs II patients showed an overall less favorable socio-demographic and clinical profile. In addition, the multivariable logistic regression showed that BD II vs BD I was predicted by the absence of lifetime suicide attempts (OR = 1.58, p = 0.01), a later age of diagnosis (OR = 1.03, p < 0.01), less hypomanic episodes in the last year (OR = 2.29, p < 0.0001) and absence of psycho-educational interventions in the last year (OR = 0.51, p < 0.01). BD I and II patients were found to significantly differ in relation to specific clinical variables, which should be considered within updated diagnostic–therapeutic algorithms.

Several studies have demonstrated that borderline personality disorder (BPD) is associated with neuropsychological deficits and there is evidence that the neurocognitive profile of patients with BPD may be related to the outcome of this disorder. The aim of this study was to investigate the feasibility and the effectiveness of a cognitive remediation intervention in patients with BPD. Thirty patients with a DSM-IV-TR diagnosis of BPD were assessed on clinical, neuropsychological and functional outcome measures at baseline and after 16 weeks of a computer-assisted cognitive remediation (CACR) intervention or treatment as usual (TAU). Patients who received CACR showed a greater improvement in working memory and psychosocial functioning measures than patients treated with TAU. Symptom severity was not significantly affected by CACR treatment. The findings of this pilot study suggest the feasibility and potential effectiveness on specific cognitive domains, but modest clinical usefulness of a computerised modality of cognitive remediation in the treatment of BPD.

none 28 no BACKGROUND: The study aimed to subtype patients with schizophrenia on the basis of social cognition (SC), and to identify cut-offs that best discriminate among subtypes in 809 out-patients recruited in the context of the Italian Network for Research on Psychoses. METHOD: A two-step cluster analysis of The Awareness of Social Inference Test (TASIT), the Facial Emotion Identification Test and Mayer-Salovey-Caruso Emotional Intelligence Test scores was performed. Classification and regression tree analysis was used to identify the cut-offs of variables that best discriminated among clusters. RESULTS: We identified three clusters, characterized by unimpaired (42%), impaired (50.4%) and very impaired (7.5%) SC. Three theory-of-mind domains were more important for the cluster definition as compared with emotion perception and emotional intelligence. Patients more able to understand simple sarcasm (⩾14 for TASIT-SS) were very likely to belong to the unimpaired SC cluster. Compared with patients in the impaired SC cluster, those in the very impaired SC cluster performed significantly worse in lie scenes (TASIT-LI

The use of inpatient and outpatient psychiatric services were assessed in the 12 months before and after a cognitive remediation (CR) intervention or treatment as usual (TAU) in a sample of 84 patients with schizophrenia who previously underwent an effectiveness study of CR. A smaller number and shorter duration of hospitalizations in acute wards and a higher total number of outpatient and rehabilitative interventions, as well as a more constant, intensive and articulated rehabilitation in the 12 months after the intervention were found in patients who received CR, compared with those who received TAU. CR may modify the use of psychiatric services and the patterns of care of patients with schizophrenia.

Summary Schizophrenia is a complex, heterogeneous behavioural and cognitive syndrome whose origins appear to lie in genetic and/or environmental disruption of brain development. Dysfunction of dopaminergic neurotransmission appears to contribute to the genesis of psychotic symptoms but the evidence also points to a more widespread and variable involvement of brain areas and circuits. There is emerging evidence that disturbances of synaptic function might underlie abnormalities of neuronal connectivity possibly involving interneurons, but the precise nature, location and timing of these events is uncertain. Current treatment consists largely in the administration of antipsychotic drugs combined with psychological therapies, social support and rehabilitation, but there is a pressing need for more effective treatments and for services to be delivered more effectively. Progress in understanding the disorder has been great in recent years with advances in genomics, epidemiology and neuroscience, and the opportunities for further scientific advance are great: but so are the challenges.

Genomic studies revealed two main components in the genetic architecture of schizophrenia, one constituted by common variants determining a distributed polygenic effect and one represented by a large number of heterogeneous rare and highly disruptive mutations. These gene modifications often affect neural transmission and different studies proved an involvement of metabotropic glutamate receptors in schizophrenia phenotype. Through the combination of literature information with genomic data from public repositories, we analyzed the current knowledge on the involvement of genetic variations of the human metabotropic glutamate receptors in schizophrenia and related endophenotypes. Despite the analysis did not reveal a definitive connection, different suggestive associations have been identified and in particular a relevant role has emerged for GRM3 in affecting specific schizophrenia endophenotypes. This supports the hypothesis that these receptors are directly involved in schizophrenia disorder.

After 2002, an association between stroke and antipsychotic use was reported in clinical trials and large database studies. This review considers previous quantitative reviews, newly published clinical trials, and recent observational cohort and case-control studies, and focuses on the clinical significance of the risk for stroke, the difference between typical and atypical antipsychotics, the possible at-risk patient profile and the timing of stroke after exposure. A search of MEDLINE covering the period from 1966 to June 2009 was carried out using selected keywords. Inclusion criteria were (i) quantitative reviews on stroke and antipsychotics; (ii) double-blind, placebo-controlled clinical trials involving patients with dementia treated with antipsychotics; and (iii) observational database cohort studies and observational case-control studies investigating the association between stroke and antipsychotics. Clinical trials were excluded if they were single-blind or if patients were affected by dementia and/or other neurological illnesses. Four reviews with aggregate data, 2 meta-analyses, 13 randomized, double-blind, controlled trials, 7 observational cohort studies and 4 observational case-control studies were selected and analysed. The incidence of cerebrovascular accidents (CVAs) was found to be very low in aggregate reviews and meta-analyses (2-4%). When the number collected was sufficiently high, or different drug treatments were grouped together, the higher rate in subjects exposed to antipsychotics was statistically significant. Inspection of other randomized controlled clinical trials, not included in aggregate reviews and meta-analyses, reported similar rates of CVAs. The majority of observational cohort studies compared typical and atypical antipsychotics and no significant class differences were found. A comparison with non-users was carried out in some cohort studies. In case-control studies, the probability of CVAs in users compared with non-users was in the range of 1.3- to 2-fold greater. Preliminary data also indicate that the highest risk of stroke is related to the first weeks of treatment, and a risk profile for stroke is emerging, such as older age, cognitive impairment and vascular illness. Different pathophysiological pathways may be involved, ranging from the facilitation of thrombosis, pre-existing cardiovascular factors, sedation and a common diathesis for stroke of dementia, schizophrenia and affective illness. Before prescribing an antipsychotic, clinicians should weigh all the risk factors for a given patient and consider not only the indications as provided by the regulatory agencies, but also the overall effectiveness of typical and atypical antipsychotics.

To test the efficacy of a training course on the diagnosis and treatment of schizophrenia, tailored for the general practitioner.A course, in a 3-session format, was given to 215 primary care doctors from the city of Brescia and its province, in Italy. All 706 doctors working in primary care were asked to participate. Of these doctors, 30.5% took part in the study. The first session (215 doctors) assessed baseline knowledge of schizophrenia (June 2002), the second (173 doctors) gave formal teaching and assessed post-lesson knowledge (October 2002), and the third (130 doctors) evaluated the retention of knowledge after 8 months (July 2003). The main outcome measures were total number of schizophrenia symptoms identified, total number of antipsychotics identified, and knowledge about antipsychotic-related adverse events.Post-lesson, general practitioners could identify 6.5 more symptoms (p.001) and 4.9 more antipsychotics (p.001). Compared to baseline, 71.5% vs. 15.4% of doctors had a good knowledge of antipsychotic-related adverse events. Although a loss of knowledge was found after the 8-month follow-up, knowledge at the endpoint was significantly higher than at baseline for the 3 main outcome variables (p.001).The teaching course on schizophrenia for general practitioners was effective, and the knowledge gained after teaching was stable across time.

The HLA-SD phenotype distributions of hebephrenic and paranoid schizophrenics, and of the two groups combined, in an Italian population and in a combined group from the Swedish population have been analyzed statistically. There is a significantly decreased frequency of HLA-A10 in all of these. There are some preliminary indications of an increased frequency (a positive association) for some of the other antigens of the HLA-SD series, but there is insufficient data at present for evaluating the significance of these findings. Differences between hebephrenic and paranoid schizophrenics have been detected.

Background Recent data have suggested few differences in the cognitive effects of antipsychotic medications. However, assessment of such effects can be complex, due to a number of factors. Clozapine has previously shown greater clinical and lesser cognitive benefits than other atypicals. This study compared the cognitive benefits of clozapine and ziprasidone in schizophrenia patients ( n = 130) with a history of either failure to respond to or intolerance of previous adequate antipsychotic treatments. Methods Patients were randomized (double-blind) to either clozapine or ziprasidone in a single country (Italy), multi-site trial. The cognitive assessments examined episodic memory (RAVLT), executive functioning (Stroop test), and processing speed (Trail-making test (TMT) Parts A and B). Results Analyses found statistically significant within-group improvements for ziprasidone in learning and delayed recall on the RAVLT and on TMT Parts A and B. Clozapine-treated patients improved on the RAVLT, but not on the TMT. A composite cognitive score improved from baseline in both groups, but the improvements were significantly larger in the ziprasidone group ( p = .029). Implications These results indicated that cognitive functioning improved following treatment with ziprasidone in patients with a history of either treatment resistance or intolerance, and that the effects are comparable or greater than those observed with clozapine. One interpretation of these findings is that clozapine treatment interferes with the performance benefits associated with practice.

Objective. To investigate the maintained efficacy of antipsychotic therapy in stable patients with bipolar disorder transitioned directly to risperidone long-acting injectable (RLAI). Methods. Within a large multi-centre European trial (StoRMi), adults with bipolar I disorder (DSM-IV) stable on a medication regimen for ≥1 month, but requiring a change of antipsychotic therapy, received injections of RLAI 25mg i.m. (increased to 37.5 or 50 mg if necessary), every 14 days for 6 months. Results. Sixteen patients were included in this subgroup analysis. Reasons for changing to RLAI included non-compliance (eight patients), insufficient efficacy (four patients) and side effects (three patients), associated with previous therapy. Twelve patients completed the 6-month trial. The most common dosage at endpoint was 25mg (seven patients). Disease symptoms (CGI Disease Severity) were significantly reduced from baseline to endpoint (P=0.0225). Patient satisfaction with treatment increased from baseline to endpoint, with 36% of patients rating their treatment satisfaction as "very good" versus 0% at baseline. Mean total score of ESRS improved from baseline to endpoint. Conclusion. Patients with bipolar disorder showed maintained symptom control over a 6-month treatment period with RLAI. Controlled studies in this population are required.

Impairment of glutamatergic neurotransmission is one of the major hypotheses proposed to explain the neurobiology of schizophrenia. Therefore, the genes involved in the glutamate neurotransmitter system could be considered potential candidate genes for schizophrenia susceptibility. A systematic study on alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor genes has been carried out and the results obtained from the analysis on GRIA2, GRIA3 and GRIA4 are reported. No evidence of association with schizophrenia was found for the GRIA2 and GRIA4 genes; strong evidence of association with schizophrenia was found for GRIA3. This X-linked gene showed a different behavior in the two genders; a positive association with schizophrenia was observed among females but not in males. Female carriers of rs1034428 A allele were found to have a 2.19-fold higher risk of developing schizophrenia compared to non-carriers and 3.28-fold higher risk for developing a non-paranoid phenotype. The analysis at the haplotype level showed that susceptibility to schizophrenia was associated with the specific haplotype rs989638–rs1034428–rs2227098 CAC (P = 0.0008). We conclude that, of the three AMPA genes analyzed here, only GRIA3 seems to be involved in the pathogenesis of schizophrenia, but only in females. © 2007 Wiley-Liss, Inc.

A number of studies support a possible link between mitochondrial dysfunction and schizophrenia. To test the hypothesis of a direct contribution of mitochondrial DNA (mt-DNA) in susceptibility to DSM-IV-TR-schizophrenia, we looked for differences in the frequency distribution of the major European haplogroups (hgs) in 142 patients and 190 controls both of Italian origin. A subgroup of patients (N = 37) and healthy counterparts (N = 41) was also analyzed for possible differences in the relative amount of mt-DNA versus nuclear-DNA in blood cells. Patients and controls were comparable for hg frequency distribution and the relative levels of mt-DNA even after stratification by gender and schizophrenia subtype. However, patients harboring the hg J-T showed an anticipated onset of the disorder. These results indicate that the J-T hg of mt-DNA may have a modulator effect on deeper determinants of schizophrenia.

In recent years, the standard for successful treatment of major depression has switched from response to remission; however, little is known about patients who have achieved remission, but still have some residual symptoms and whether they regain previous levels of functioning. In a large, nationwide, cross-sectional, naturalistic survey (VIVAL-D) of 907 patients with major depression treated with a new course of an antidepressant in 41 Italian community psychiatric centers, patients with a Hamilton Rating Scale for Depression, 17-item version (HAM-D17) score up to 14 were selected (n=499). Of these, 169 were considered to be in remission (HAM-D17 ≤ 7) and the other 330 to be mildly depressed. Their level of functioning was evaluated using the SF-12. Only a few (3%) patients in remission were completely symptom free; most were affected by residual symptoms. Patients in remission had better SF-12 scores than those with mild depression, but their functioning was significantly worse than general population norms. In the logistic regression analysis, the HAM-D17 total score and individual items were predictive of poor functioning. Analysis of sensitivity and specificity values showed that a lower cut-off score (4/5) of the HAM-D17 scale was best for predicting poor performance so that a reconsideration of the usual cut-off for remission of 7/8 for HAM-D17 seems overdue.

The search for biomarkers of response to antipsychotic medications is hindered by difficulties inherent in the topic or related to persistent methodological difficulties, such as high rates of anticipated discontinuation and consequent distortions in the imputation of missing data. Because early response to antipsychotics represents a sufficiently reliable index of the subsequent treatment response in patients with schizophrenia, we undertook a real-world, genome-wide association study (GWAS) with the aim of identifying genetic predictors of response to risperidone after 2 weeks in 86 patients with schizophrenia. Limited to the associations reaching significance in the GWAS, confirmatory analysis relative to risperidone response over 9 months was also designed involving 97 patients (European only) enroled in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) genetic substudy. The GWAS revealed a significant association (false discovery rate 0.02) of the single-nucleotide polymorphism rs2133450 inside the GRM7 gene with Emsley's positive domain derived from the positive and negative syndrome scale (PANSS). Patients with the rs2133450 CC genotype presented poorer improvement in the positive domain over 2 weeks, with odds ratios of 12.68 (95% CI, 3.51-45.76) and 6.95 (95% confidence interval (CI), 2.37-20.37) compared with patients with the AA and AC genotypes, respectively. Compared with A homozygotes, rs2133450 C homozygotes enroled in the CATIE-derived confirmatory analysis showed less improvement in Emsley's positive, excited and depression domains, positive and general PANSS subtypes, and total PANSS after 9 months of treatment with risperidone. The original GWAS and the CATIE-derived confirmatory analysis support the proposal that the rs2133450 may have translational relevance as a predictor of response to risperidone.

Major depressive disorder (MDD) is a common, chronic disorder that requires long-term management. Although effective treatments are available, MDD frequently remains undiagnosed. Furthermore, once recognized, treatment duration and dosage are often inadequate and adherence to medication is often poor. However, adequate acute phase treatment of MDD is essential to reduce symptomatology, and improve quality of life and the clinical course. After remission, treatment should be continued for 4-9 months to consolidate the remission and prevent relapse. For patients who do not respond adequately to their initial antidepressant therapy, switching or augmentation of therapy may be necessary. Many patients suffer residual symptomatology, even when classified as being in remission. In addition to the suffering and impairment that this causes, residual symptomatology is associated with a high rate of relapse. Clinicians should strive to achieve asymptomatic recovery both in terms of core symptomatology and psychosocial disability. This requires appropriate treatment at therapeutic doses for a sufficient duration; education and support to promote patient compliance with treatment; and regular monitoring and prompt intervention for patients with symptoms that persist even at subsyndromal levels. In conclusion, there remains considerable scope for improving the identification, treatment and management of patients with MDD.

An increasing body of evidence suggests a role for the immune system in the pathogenesis of schizophrenia. The information concerning the effects of antipsychotics on cytokine profiles are limited and often controversial in particular regarding novel antipsychotics. The authors first investigated the production of various cytokines [interleukin (IL)-2, IL-4, IL-10, interferon (INF)-gamma] in drug-free (n = 12) and drug-naive (n = 3) schizophrenic patients and in healthy controls (n = 33) and then the modifications of cytokines values during a 3-month period of treatment with risperidone. In the baseline condition, the production of IL-2 and INF-gamma was significantly higher (P = .023 and .026, respectively) in patients than in controls. In the same patients, the use of risperidone was associated with augmented IL-10 (a suppressor of Type I cytokines) and decreased INF-gamma production. This modification suggests that clinical improvement is associated with a reduction in the inflammatory-like situation present in not currently treated schizophrenic patients.

Inbreeding is a known risk factor for recessive Mendelian diseases and previous studies have suggested that it could also play a role in complex disorders, such as psychiatric diseases. Recent inbreeding results in the presence of long runs of homozygosity (ROHs) along the genome, which are also defined as autozygosity regions. Genetic variants in these regions have two alleles that are identical by descent, thus increasing the odds of bearing rare recessive deleterious mutations due to a homozygous state. A recent study showed a suggestive enrichment of long ROHs in schizophrenic patients, suggesting that recent inbreeding could play a role in the disease. To better understand the impact of autozygosity on schizophrenia risk, we selected, from a cohort of 180 Italian patients, seven subjects with extremely high numbers of large ROHs that were likely due to recent inbreeding and characterized the mutational landscape within their ROHs using Whole Exome Sequencing and, gene set enrichment analysis. We identified a significant overlap (17%; empirical p-value = 0.0171) between genes inside ROHs affected by low frequency functional homozygous variants (107 genes) and the group of most promising candidate genes mutated in schizophrenia. Moreover, in four patients, we identified novel and extremely rare damaging mutations in the genes involved in neurodevelopment (MEGF8) and in GABA/glutamatergic synaptic transmission (GAD1, FMN1, ANO2). These results provide insights into the contribution of rare recessive mutations and inbreeding as risk factors for schizophrenia. ROHs that are likely due to recent inbreeding harbor a combination of predisposing low-frequency variants and extremely rare variants that have a high impact on pivotal biological pathways implicated in the disease. In addition, this study confirms that focusing on patients with high levels of homozygosity could be a useful prioritization strategy for discovering new high-impact mutations in genetically complex disorders.

Suicide is a serious public health problem worldwide, and many nations are committed to developing prevention programmes to reduce the incidence of suicide. To date, several strategies have been proposed for suicide prevention, both at the population and at the individual level, some of which may be pharmacological. In particular, a substantial amount of data show that lithium significantly reduces mortality in patients with mood disorders. Initiating from this evidence, some recent studies have investigated whether a relationship might exist between levels of lithium in drinking water and mortality rates for suicide in the general population. We have systematically reviewed all the articles published on this issue to date. The available literature indicates that higher lithium levels in drinking water may be associated with reduced risk of suicide in the general population.

La schizofrenia rimane tuttora uno dei disturbi mentali piu gravi, specie sotto il profilo del funzionamento psicosociale e relazionale di chi ne e affetto. L’inadeguatezza delle interazioni interpersonali e la marcata alterazione delle abilita sociali sono, infatti, tra le caratteristiche piu costanti e invalidanti del disturbo. Negli ultimi anni, abbiamo assistito a un cambiamento di prospettiva nella ricerca sulla schizofrenia, con l’interesse primario che si e spostato progressivamente dall’obiettivo di ridurre la gravita della sintomatologia, in particolare di quella «positiva» (deliri, allucinazioni, disorganizzazione) a quello di migliorare il «funzionamento» e l’integrazione sociale del soggetto (Green e Horan, 2010). E in questo contesto che lo studio della cognitivita, della cognitivita sociale e dei loro deficit e diventato un ambito di grande interesse per il clinico e per il ricercatore.

article i nfo Article history: Objectives: Cognitive remediation interventions are effective in patients with schizophrenia, but the durability of their effects is still under debate. This study aimed to investigate the 1-year persistence of the effectiveness of cognitive remediation. Methods:Patients with schizophrenia treated with cognitive remediation or usual rehabilitation were reassessed with clinical, neuropsychological and functional measures 1 year after cognitive remediation. Results: At the 1-year follow-up, the advantages of cognitive remediation remained significant for clinical vari- ables and specific cognitive domains. Functional measures showed increasing improvement at follow-up. Conclusions: The study suggests that the effectiveness of cognitive remediation in schizophrenia persists after 1y ear.

BACKGROUND AND PURPOSE: Previous studies have suggested that structural changes do occur in the brain of patients with schizophrenia compared with healthy control participants. However, findings from such studies are inconclusive, probably because of the different methodologic approaches, the clinical heterogeneity of patient samples, and also the fact that patients enrolled were treated with antipsychotic drugs. The aim of this study was to investigate brain GM volumes and intrinsic structural WM changes in first-contact, antipsychotic drug-naive patients with schizophrenia. MATERIALS AND METHODS: A total of 43 first-contact, drug-naive, patients with schizophrenia and 17 age-matched control participants were studied. All participants underwent T1-weighted MR imaging and DTI scans. Voxel-based morphometry and tract-based spatial statistics were used to compare GM volumes and WM DTI metrics between groups. MR imaging measures were correlated with the duration of the untreated psychosis and the clinical positive and negative symptoms. RESULTS: Compared with control participants, patients with schizophrenia showed smaller volumes of the temporal, parietal, and occipital GM, and a pattern of decreased mean diffusivity and increased fractional anisotropy in the brain stem and cerebellum bilaterally, interhemispheric and cortico-cortical connections bilaterally, and right anterior and posterior limb of the internal capsule. In patients, decreased mean diffusivity and increased fractional anisotropy in several brain regions were related to a longer duration of the untreated psychosis and the severity of positive symptoms. CONCLUSIONS: First-contact, drug-naive, patients with schizophrenia present with volumetric and DTI changes, which correlated with their clinical features. This study increases our knowledge on the neural networks involved in the pathophysiologic mechanisms of schizophrenia.

1 Poor adherence to antipsychotic medication in people with schizophrenia: diffusion, consequences, and contributing factors.- Premise.- Role of antipsychotics in the treatment of schizophrenia.- Compliance versus adherence.- Assessment of medication adherence.- Frequency of poor adherence to antipsychotics.- Consequences of poor adherence to antipsychotics.- Determinants and moderators of adherence to antipsychotics.- Present and medium-term perspectives.- Closing Remarks.- 2 Pharmacological strategies to enhance adherence in schizophrenia.- Introduction.- Pharmacological factors contributing to non-adherence: efficacy, side effects, regimen, co-therapies.- First vs Second generation antipsychotics: efficacy, tolerability and the adherence issue.- Long-acting injectable antipsychotics.- Conclusion. 3 Non-pharmacological strategies to enhance adherence and continuity of care in schizophrenia.- Introduction.- Factors Influencing (non-)adherence in Schizophrenia.- Interventions to Enhance Adherence. Research and Clinical Evidence.- Comprehensive Review of Psychosocial and Programmatic Interventions to Enhance Adherence to Antipsychotic Medication in Schizophrenia.- Summary of Main Results and Evidences.- Conclusions and Future Directions.- 4 Psychological issues in improving adherence and alliance.- The patient-doctor relationship as a determinant of adherence to treatment.- Alliance and psychodynamic issues.- Towards the concept of concordance of the therapeutic project.

Nonadherence is highly prevalent in schizophrenia. It has been estimated that nonadherence rate for prescribed antipsychotic medications is about 50 %. Nonadherence with antipsychotic medication is a major cause of relapse and it is associated with poorer functional outcomes in patients with schizophrenia. After identifying factors that may be contributing to a patient’s adherence, it is important for clinicians to initiate strategies specifically targeted to those problems. Research has increasingly focused on psychosocial and pharmacological interventions to improve outcomes in patients with schizophrenia. Systematic reviews of various psychosocial approaches to enhance adherence to medication in schizophrenia indicate that some approaches have yielded some promising results, but they are still controversial or preliminary. The aim of this chapter is to provide a comprehensive overview of the available data on nonpharmacological strategies designed to improve adherence to medication in schizophrenia. Interventions and strategies proposed and/or tested to enhance adherence to antipsychotic medication are systematically described and discussed.

This chapter tries to present the issue of poor adherence to treatment in people with schizofrenia, by treating the following topics: role of antipsychotics in the treatment of schizophrenia, compliance versus adherence, assessment of medication adherence, frequency of poor adherence to antipsychotics and consequences of poor adherence to antipsychotics present and medium-term perspectives.

Objective Although the efficacy of cognitive remediation interventions has been demonstrated in several experimental studies on schizophrenia, few studies have investigated the predictors of response to such interventions. We were interested in determining what factors contribute to a positive outcome after cognitive rehabilitation and whether different factors are associated with different degrees of improvement in cognitive and real-world functioning in individual patients after cognitive remediation. Methods The study sample consisted of 56 patients with schizophrenia who had completed a 6-month cognitive remediation intervention and showed different cognitive and functional outcomes. Measures of cognitive and functional amelioration after cognitive remediation were analyzed in relation to patients' clinical, neuropsychological and functional variables at baseline using logistic regression analysis. Results Lower antipsychotic intake at baseline predicted cognitive improvement, whereas lower antipsychotic intake, severity of specific symptoms, and higher neurocognitive functioning (particularly executive functions and verbal memory) at baseline were associated with cognitive normalization after remediation treatment. Functional improvement was predicted by lower patient age and type of cognitive remediation intervention, whereas functional normalization was related to lower baseline antipsychotic intake and, at a trend level, to higher executive functioning and type of cognitive remediation intervention. Conclusion Cognitive remediation could be more effective in younger, less disorganized, and cognitively less impaired patients, who take a smaller amount of antipsychotics. The predictive role of lower antipsychotic dosage on cognitive and functional outcome after remediation suggests either that patients with less severe illness could gain better advantage from cognitive remediation interventions or that high dose or complex antipsychotic therapy may limit the effectiveness of such interventions.

Background Recent studies supported associations between four NMDA-receptor-mediated signalling genes (D-amino acid oxidase, DAO; D-amino acid oxidase activator, DAOA; protein phosphatase 3 catalytic subunit gamma isoform, PPP3CC; dystrobrevin-binding protein 1, DTNBP1) and schizophrenia susceptibility, even though with contrasting results. Methods In an attempt to replicate these findings for the first time in an Italian population, a panel of 32 tagSNPs was analysed in a representative case-control sample involving 879 subjects. Results An association in the allele frequency was observed for the estimated PPP3CC CAG triplotype in the SNP window rs4872499 T/C-rs11780915 A/G-rs13271367 G/A (pcorrect = 0.001). Similarly, the clustered genotype frequencies of the estimated/phased CAG triplotype differed between cases and controls (p = 0.004), with the carriers having a higher frequency in the control population (p = 0.002, odd ratio OR = 0.59, 95% confident interval CI: 0.43-0.82). Following the phenotypic dissection strategy, the analysis of single SNPs evidenced a protective effect in males of rs11780915 and rs13271367 in PPP3CC gene (pcorrect = 0.02, pcorrect = 0.04 respectively). Moreover the estimated/phased GT diplotype (rs2070586A/G-rs3741775G/T) carriers of the DAO gene were more highly represented in female controls (p = 0.017, OR = 0.58, 95% CI: 0.37-0.90), as were the estimated/phased CAG triplotype carriers of the PPP3CC gene in females (p = 0.01, OR = 0.53, 95% CI: 0.32-0.87). In addition, we performed an interaction analysis, and a 66% (p = 0.003, OR = 0.34, 95% CI: 0.17-0.70) lower risk of developing schizophrenia for female (CAG + GT) carriers versus non-CAG or -GT carriers was observed. For DTNBP1, we found a protective effect in males for the rs6459409 (pcorrect = 0.02) and the estimated/phased CT diplotype (rs6459409-rs9476886) carriers (p = 3x10-4 , OR = 0.46, 95% CI: 0.30-0.70). In relation to diagnostic subtypes, the estimated/phased DAO GT diplotype and PPP3CC CAG triplotype female carriers were found to show relative risk ratio (RRR) values of 0.52 and 0.54 lower risk for a paranoid phenotype respectively. Conclusions Although the results are preliminary and needed replication in a larger sample, this study suggests that NMDA receptor-mediated signalling genes (DAO, PPP3CC, DTNBP1) might be involved in schizophrenia pathogenic mechanisms related to gender.

The aim of this study was to quantitatively review, using a meta-analytic approach, randomized-controlled trials analyzing the efficacy and safety profiles of asenapine in the treatment of bipolar disorder (BD). MEDLINE (1966 to August 2012) and EMBASE (1980 to August 2012) databases were systematically searched to identify relevant papers. Data from four randomized-controlled trials were analyzed. For continuous data (Young Mania Rating Scale, Clinical Global Impression Scale for Bipolar Disorder, and Montgomery-Asberg Depression Rating Scale scores), the Hedges g was adopted as a measure of the effect size; for dichotomous outcome measures (discontinuation and rates of adverse events), the risk ratio was calculated. In short-term trials, asenapine was found to be significantly superior to placebo in the treatment of manic symptoms of BD. There is also evidence of the positive effects of asenapine compared with placebo on depressive symptoms in mixed bipolar states. In the medium-term and long-term studies, asenapine showed comparable efficacy with the well-established comparator olanzapine in the treatment of manic and depressive symptoms of BD. Adverse events such as somnolence, weight gain, and extrapyramidal symptom, which have an impact on treatment adherence, are scarcely or moderately elicited by asenapine, which shows a better profile than olanzapine on metabolic parameters. On the basis of these results, asenapine can be considered as an effective and tolerable treatment for manic and mixed episodes of BD.

In a controlled, randomized, multicenter, double-blind study involving 335 patients with generalized anxiety disorder, buspirone (Busp) was compared to lorazepam, diazepam or bromazepam in order to test its global efficacy, preferential effectiveness in defined subgroups of patients or symptoms, latency of action and safety and tolerability. Apart from minor differences, the dropout rate, the number of subjects for whom the dose was increased, the number of capsules taken daily, the modifications of HRSA, VAS 100 mm, CGIS and CGSRS, the curves of improvement over time, the effectiveness on the somatic and psychic factors of the HRSA, the responsiveness of depressed and non-depressed anxious patients, and the profiles of adverse events indicated clinical equivalence between the azaspirodecanedione and the comparison benzodiazepines.

The aim of this study was to quantitatively review randomized controlled trials (RCTs) and open-label trials analyzing the efficacy of antidepressants, mood stabilizers, and antipsychotics for the treatment of the core symptoms of borderline personality disorder (BPD). Using a similar meta-analytic approach, the efficacy of placebo on the same core symptoms of BPD was evaluated. The risk of discontinuation of each of the medication classes reported in the studies was also analyzed to establish the major causes of discontinuation. MEDLINE (1966 to June 2010) and EMBASE (1980 to June 2010) databases were systematically searched to identify relevant RCTs and open studies. The primary outcome was improvement in the specific core symptoms of the disorder: affective dysregulation, impulsive-behavioral dyscontrol, and cognitive-perceptual symptoms. Evidence from RCTs and open studies suggests that drug treatment, especially with mood stabilizers and antipsychotics, may be effective for treating affective dysregulation and impulsive-behavioral dyscontrol. Antipsychotics were also effective in reducing cognitive-perceptual symptoms. Antidepressants failed to show efficacy in treating BPD symptom dimensions other than affective dysregulation. Our analyses of the placebo arm of RCTs showed a significant improvement of symptomatology in these patients also. There were no significant differences in overall dropout rates between patients on medications and those on placebo. In conclusion, the efficacy of pharmacological treatment on the symptom dimensions of BPD has been shown by various independent meta-analyses, with a positive effect of drug treatment on the core symptoms of BPD and some documentable differences in terms of efficacy between different drug classes in each of the symptom domains.