Association study between HTR2A rs6313 polymorphism and early response to risperidone and olanzapine in schizophrenia patients.

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.

Well-being in patients with schizophrenia, mood and personality disorders attending psychiatric services in the community. A controlled study.

BACKGROUND: Poor attention is paid by recent research to the prevalence of mental well-being in psychiatric patients and the comparison between groups with different diagnoses. Data suggest that the presence of mental illness does not necessarily mean the absence of well-being, particularly in stable outpatients. METHODS: A consecutive series of 375 patients attending two community mental health centers was given the Mental Health Continuum Short Form (MHC-SF) and the Clinical Global Impression - Severity scale. Diagnoses were made after the MINI Neuropsychiatric Interview and a chart review of all relevant clinical information. The flourishing category and the three components of MHC-SF were used to rate well-being. A total of 274 controls were taken from the employees at a local firm. RESULTS: The rates of flourishing mental health were: 33.1% schizophrenia, 36.6% bipolar disorder, 23.3% unipolar depression, 24.4% cluster B personality disorder, and 53.3% controls (p < 0.001). The comparison of the three MHC components across diagnostic groups found that unipolar depression and cluster B personality patients had significantly lower scores compared to bipolar and schizophrenia patients. Flourishing mental health was detected more often in males than females (34.9% vs. 24.1% - p < 0.05). For schizophrenia patients indices of well-being were better in those on depot medications. CONCLUSIONS: Psychiatric outpatients with major mental illness have lower rates of well-being compared to controls, although about one-third is flourishing. Patients with unipolar depression and cluster B personality disorder may deserve special attention when planning intervention for fostering well-being.

A miR-137-Related Biological Pathway of Risk for Schizophrenia Is Associated With Human Brain Emotion Processing.

BACKGROUND: miR-137 is a microRNA involved in brain development, regulating neurogenesis and neuronal maturation. Genome-wide association studies have implicated miR-137 in schizophrenia risk but do not explain its involvement in brain function and underlying biology. Polygenic risk for schizophrenia mediated by miR-137 targets is associated with working memory, although other evidence points to emotion processing. We characterized the functional brain correlates of miR-137 target genes associated with schizophrenia while disentangling previously reported associations of miR-137 targets with working memory and emotion processing. METHODS: Using RNA sequencing data from postmortem prefrontal cortex (N = 522), we identified a coexpression gene set enriched for miR-137 targets and schizophrenia risk genes. We validated the relationship of this set to miR-137 in vitro by manipulating miR-137 expression in neuroblastoma cells. We translated this gene set into polygenic scores of coexpression prediction and associated them with functional magnetic resonance imaging activation in healthy volunteers (n1 = 214; n2 = 136; n3 = 2075; n4 = 1800) and with short-term treatment response in patients with schizophrenia (N = 427). RESULTS: In 4652 human participants, we found that 1) schizophrenia risk genes were coexpressed in a biologically validated set enriched for miR-137 targets; 2) increased expression of miR-137 target risk genes was mediated by low prefrontal miR-137 expression; 3) alleles that predict greater gene set coexpression were associated with greater prefrontal activation during emotion processing in 3 independent healthy cohorts (n1, n2, n3) in interaction with age (n4); and 4) these alleles predicted less improvement in negative symptoms following antipsychotic treatment in patients with schizophrenia. CONCLUSIONS: The functional translation of miR-137 target gene expression linked with schizophrenia involves the neural substrates of emotion processing.

Schizophrenia susceptibility and NMDA-receptor mediated signalling: an association study involving 32 tagSNPs of DAO, DAOA, PPP3CC, and DTNBP1 genes.

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.

Adult ADHD and sleep disorders: Prevalence, severity and predictors of sleep disorders in a sample of Italian psychiatric outpatients.

OBJECTIVE: Sleep disorders are frequent in adult subjects diagnosed with ADHD. The aims of the present study were to assess the prevalence and the severity of sleep disorders in a sample of Italian psychiatric outpatients, to compare the prevalence and severity of sleep disorders in patients with and without diagnosis of adult ADHD, and to evaluate the role of ADHD as an individual predictor of sleep disturbances severity. 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. Sleep disorders and sleep disturbances' severity were assessed with the PROMIS Adult Sleep Disturbance Scale. RESULTS: Sleep disorders were more frequent (p < 0.001) and sleep disturbances were more severe (d = 1.26, p < 0.001) in subjects diagnosed with adult ADHD compared to other outpatients. Among the 44 subjects diagnosed with ADHD, 15 (34.1%) reported no or slight sleep disturbances, 9 (20.5%) a mild sleep disorder, 17 (38.6%) a moderate sleep disorder and 3 (6.8%) a severe sleep disorder. ADHD diagnosis, multiple psychiatric comorbidity and history of suicide attempts emerged as individual predictors of worse sleep disturbances. CONCLUSION: Sleep disorders are more frequent and severe in subjects diagnosed with ADHD compared to other adult outpatients. Sleep disturbances might represent an intrinsic feature in adult ADHD subjects, presenting important clinical repercussions, and should be routinely evaluated and monitored in this population.

Primary and secondary negative symptoms severity and the use of psychiatric care resources in schizophrenia spectrum disorders: A 3-year follow-up longitudinal retrospective study.

Negative symptoms represent one of the core features of schizophrenia spectrum disorders (SSD), strongly correlated with low remission rates, poor real-world functioning, and worse quality of life. Despite the body of evidence attesting the role of negative symptoms in determining worse outcomes in SSD, few studies have directly investigated their impact on the use of psychiatric services and even fewer research have examined the differential impact between primary versus secondary negative symptoms. The present study aims to investigate whether SSD subjects with high levels of primary and of secondary negative symptoms at an index hospitalization show a different use of psychiatric services in the subsequent 3 years. A total of 429 subjects were included in the study. Results show that SSD patients with high levels of negative symptoms are characterized by an overall greater use of high-cost resources, with more admissions in the hospital acute care psychiatric ward and in high intensity residential inpatient services. Moreover, while primary negative symptoms appear to play a role in determining a greater use of psychiatric services, high levels of secondary negative symptoms are associated with an increased use of most psychiatric resources, especially of high-cost ones. In conclusion, negative symptoms have a relevant impact on the pattern of psychiatric resources utilization in SSD patients. While scientific research continues to look for effective treatments for primary negative symptoms, clinicians should pay particular attention to secondary negative symptoms, as these also have important consequences but may benefit from appropriate treatment.

Internalized stigma among people with schizophrenia: Relationship with socio-demographic, clinical and medication-related features.

BACKGROUND: People with schizophrenia are at high risk of suffering from stigma and internalizing it. Recently, a better understanding of the stigma process has shifted the attention from public stigma to self-stigma, which is deeply debilitating. This study aimed to assess factors associated to self-stigma by evaluating socio-demographic, clinical and treatment-related variables in a group of subjects diagnosed with schizophrenia and to identify predictors of high internalized stigma. METHODS: Ninety-four inpatients accessing rehabilitative centers with a diagnosis of schizophrenia were included in this cross-sectional study. Measures included both patient-rated scales, assessing internalized stigma, attitude toward medications, side effects experience and subjective well-being, and clinician-rated scales, assessing schizophrenia symptoms and global clinical severity and antipsychotic-related side effects. RESULTS: Twenty-one patients (22.3%) showed high internalized stigma while 73 (77.7%) did not. Patients experiencing more medication adverse effects and worse subjective well-being were more likely to suffer from internalized stigma according to a logistic regression analysis. Extrapyramidal, psychic and some autonomic reactions also emerged as individual predictors of self-stigma in a separate regression analysis. CONCLUSIONS: Self-stigma and subjective medication side effects perception represent a relevant issue in patients' life and should be carefully taken into account in clinical practice.

Autistic Symptoms in Schizophrenia: Impact on Internalized Stigma, Well-Being, Clinical and Functional Characteristics.

Autism Spectrum Disorders (ASD) symptoms and internalized stigma (or self-stigma) can have a negative impact on cognitive and functional outcomes in people living with schizophrenia. Aim of the present study were to assess and compare internalized stigma, subjective well-being and other socio-demographic, clinical and functional characteristics in people diagnosed with schizophrenia with and without prominent autistic features. Ninety-four inpatients were assessed with measures of internalized stigma, subjective well-being, global clinical severity, schizophrenia symptoms severity, real-world functioning, medication side effects and attitude toward prescribed medications. Subjects with high levels of ASD symptoms were identified with the PANSS Autism Severity Score and compared to other participants. Predictors of prominent ASD features were also assessed. Thirteen patients showed prominent ASD symptoms. They were characterized by fewer years of education, worse real-world functioning and greater symptoms severity. No between-group differences were observed regarding subjective well-being and global internalized stigma severity; however, participants in the "autistic schizophrenia" group showed better stigma resistance. A worse clinical condition and fewer years of education emerged as predictors of autistic schizophrenia. Despite showing a more severe clinical presentation of the disorder and worse functional impairment, participants with prominent ASD symptoms do not present worse subjective well-being or more severe internalized stigma; on the contrary, they show better stigma resistance. ASD symptoms could therefore play a protective role in the internalization of stigma.

Adult ADHD: Prevalence and Clinical Correlates in a Sample of Italian Psychiatric Outpatients.

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.

Author Correction: A novel homozygous mutation in GAD1 gene described in a schizophrenic patient impairs activity and dimerization of GAD67 enzyme.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Reduced fractional anisotropy of corpus callosum in first-contact, antipsychotic drug-naive patients with schizophrenia.

BACKGROUND: Corpus callosum is the most important commissure of the brain and therefore represents a first-choice candidate to challenge hypotheses of disrupted inter-hemispheric connectivity and white matter pathology in patients with schizophrenia. Recent studies on diffusion tensor imaging (DTI) of corpus callosum yielded promising but equivocal evidence of reduced fractional anisotropy (FA) in schizophrenia patients who were, for the most part, chronic cases on medication for a lengthy period of time. To exclude potentially confounding effects of the course of the disorder and its treatment, we compared callosal FA of first-contact, antipsychotic drug-naive schizophrenia patients (n=21) and healthy controls (n=21). METHODS: Splenium and genu FA were obtained by two independent observers utilizing large, rectangular, tractography-guided regions of interest outlined on directional color-coded maps. Inter-observer agreement on FA was evaluated by means of the Bland and Altman and the Passing and Bablok procedures together with an estimate of the intra-class correlation coefficient. RESULTS: Strong inter-observer agreement of FA values emerged from each of the three statistical approaches utilized. ANCOVA showed a significant effect on FA for the interaction between patient-control membership and callosal region (F=5.354; p=0.026); post hoc multiple comparisons demonstrated that, when compared to the controls, the patients had lower mean FA values (p=0.005) in the splenium but not in the genu and that this difference tended to be more evident in males (p=0.090). CONCLUSIONS: Lowered mean FA values in the splenium of first-contact, antipsychotic drug-naive patients with respect to healthy controls strongly support the hypothesis that processes operant at least since the earliest phases of the disorder and independent from exposition to antipsychotic drugs contribute to reduced anisotropy in schizophrenia.

Ziprasidone vs clozapine in schizophrenia patients refractory to multiple antipsychotic treatments: the MOZART study.

This 18-week, randomized, flexible-dose, double-blind, double-dummy trial evaluated ziprasidone as an alternative to clozapine in treatment-refractory schizophrenia patients. Patients had a DSM-IV diagnosis of schizophrenia, a history of resistance and/or intolerance to at least three acute cycles with different antipsychotics given at therapeutic doses, PANSS score >or=80, and CGI-S score >or=4. Patients were randomized to ziprasidone (80-160 mg/day, n=73) or clozapine (250-600 mg/day, n=74). On the primary ITT-LOCF analysis, baseline-to-endpoint decreases in PANSS total scores were similar in the ziprasidone (-25.0+/-22.0, 95% CI -30.2 to -19.8) and clozapine (-24.5+/-22.5, 95% CI -29.7 to -19.2) groups. A progressive and significant reduction from baseline in PANSS total score was observed from day 11 in both study arms. There were also significant improvements on PANSS subscales, CGI-S, CG-I, CDSS, and GAF, without between-drug differences. The two treatment groups had similar rates of early discontinuations due to AEs. AEs were mostly of similar mild-moderate severity in the two groups. There were also no detrimental effects on prolactin, renal and liver function, hematology, and cardiovascular parameters. However, ziprasidone but not clozapine showed a significant reduction of SAS and AIMS scores. Moreover, when compared with clozapine, ziprasidone also had a more favorable metabolic profile, with significant endpoint differences in weight, fasting glucose, total cholesterol, LDL cholesterol, and triglycerides. In conclusion, this trial indicates that both ziprasidone and clozapine, having comparable efficacy coupled with satisfactory general safety and tolerability, may be regarded as valuable options for the short-term treatment of difficult-to-treat schizophrenia patients with a history of multiple resistance and/or intolerance to antipsychotics. The more favorable metabolic profile of ziprasidone may represent an added value that could guide clinicians, at least in the presence of patients at high risk for metabolic disorders.

Esperienze di switch a cariprazina in pazienti affetti da schizofrenia con ricorrenze.

Nel trattamento a lungo termine dei pazienti affetti da schizofrenia, il problema delle ricadute di malattia è di fondamentale rilevanza clinica e tuttora dibattuto. Una possibile strategia di intervento, in caso di riacutizzazione, è quella dello switch da un farmaco antipsicotico a un altro. Sarebbe utile, in questo senso, avere a disposizione molecole in grado di garantire uno stato di remissione clinica persistente nel tempo. Fra queste è possibile senz'altro considerare cariprazina, un farmaco di recente introduzione, dotato di un profilo d'azione unico rispetto agli altri antipsicotici, sia tipici che atipici.

Effectiveness of Cognitive Remediation in Early Versus Chronic Schizophrenia: A Preliminary Report.

Background: Many evidences have demonstrated the effectiveness of cognitive remediation on cognition and functioning in patients with schizophrenia. Some researchers speculate that cognitive deficits are more amenable to remediation during earlier phases of illness than in chronicity. Therefore, cognitive rehabilitation should be used as an early intervention, seeking to produce durable functional changes in the early course of schizophrenia. Although there is strong evidence that cognitive remediation is effective in adult schizophrenia, there is little evidence about its efficacy and long-term generalized effectiveness in the early course of the disease. In this paper, we intended to investigate the possibility that cognitive remediation may produce more beneficial effects when applied in the early phase of the illness compared to chronic patients. Materials and methods: Data were gathered from a database used for a previous study performed by our group, in which 56 patients with schizophrenia received a cognitive remediation intervention. In a post hoc analysis, patients with a duration of illness shorter than 5 years were defined as "early course" patients, while patients with a duration of illness longer than 5 years were defined as "chronic." Clinical, neuropsychological, and functional outcome variables were assessed at baseline and after treatment. Result: Of the 56 patients included in the study, 11 were "early course" and 45 were "chronic." Both the early course group and the chronic group showed significant improvements in all the clinical, neurocognitive, and functional parameters analyzed. A significantly greater improvement in early course patients compared with chronic patients emerged in clinical and functional measures. No differential change was observed between early course patients and chronic patients in the cognitive composite score. Conclusion: Our study confirms the effectiveness of cognitive remediation in improving clinical, cognitive, and functional parameters in patients with schizophrenia, both in patients in the early course and in chronic patients. However, patients in the early course showed a differential, greater change in clinical and functional parameters compared to chronic patients. Although this study has some limitations, it confirms the effectiveness of cognitive remediation interventions, particularly if applied in the early course of the illness.

Paliperidone palmitate in short- and long-term treatment of schizophrenia.

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.

Treatment-Resistant Schizophrenia: Genetic and Neuroimaging Correlates.

Schizophrenia is a severe neuropsychiatric disorder that affects approximately 0.5-1% of the population. Response to antipsychotic therapy is highly variable, and it is not currently possible to predict those patients who will or will not respond to antipsychotic medication. Furthermore, a high percentage of patients, approximately 30%, are classified as treatment-resistant (treatment-resistant schizophrenia; TRS). TRS is defined as a non-response to at least two trials of antipsychotic medication of adequate dose and duration. These patients are usually treated with clozapine, the only evidence-based pharmacotherapy for TRS. However, clozapine is associated with severe adverse events. For these reasons, there is an increasing interest to identify better targets for drug development of new compounds and to establish better biomarkers for existing medications. The ability of antipsychotics to improve psychotic symptoms is dependent on their antagonist and reverse agonist activities at different neuroreceptors, and some genetic association studies of TRS have focused on different pharmacodynamic factors. Some genetic studies have shown an association between antipsychotic response or TRS and neurodevelopment candidate genes, antipsychotic mechanisms of action (such as dopaminergic, serotonergic, GABAergic, and glutamatergic) or pharmacokinetic factors (i.e., differences in the cytochrome families). Moreover, there is a growing body of literature on the structural and functional neuroimaging research into TRS. Neuroimaging studies can help to uncover the underlying neurobiological reasons for such resistance and identify resistant patients earlier. Studies examining the neuropharmacological mechanisms of antipsychotics, including clozapine, can help to improve our knowledge of their action on the central nervous system, with further implications for the discovery of biomarkers and the development of new treatments. The identification of the underlying mechanisms of TRS is a major challenge for developing personalized medicine in the psychiatric field for schizophrenia treatment. The main goal of precision medicine is to use genetic and brain-imaging information to improve the safety, effectiveness, and health outcomes of patients via more efficiently targeted risk stratification, prevention, and tailored medication and treatment management approaches. The aim of this review is to summarize the state of art of pharmacogenetic, pharmacogenomic and neuroimaging studies in TRS.

Paliperidone extended-release in the short- and long-term treatment of schizophrenia.

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.

A randomized, flexible-dose, quasi-naturalistic comparison of quetiapine, risperidone, and olanzapine in the short-term treatment of schizophrenia: the QUERISOLA trial.

This was a randomized, flexible-dose, rater-blind, parallel-group, quasi-naturalistic trial comparing the efficacy, safety, and tolerability of quetiapine, risperidone, and olanzapine in patients with schizophrenia hospitalized for severe psychotic symptoms. Seventy-five patients were randomized to quetiapine (n=25), risperidone (n=25), or olanzapine (n=25). Mean doses at Week 8 were: 590.0 mg/day quetiapine; 5.1 mg/day risperidone; 15.1 mg/day olanzapine. Four quetiapine, five risperidone, and five olanzapine patients discontinued prior to Week 8. There were no significant differences between groups in the primary efficacy measures of improvement from baseline in Positive and Negative Syndrome Scale (PANSS) total score at Week 8 in the per protocol (PP) population and the number of completers who experienced >or=40% improvement on the same scale. PP and intent-to-treat analyses showed significant improvement from baseline in each component of a PANSS-derived battery, without significant differences between treatments. No quetiapine patients, one risperidone, and four olanzapine patients reported an adverse event (AE) of moderate intensity; no severe AEs were reported. A linear mixed model for repeated measures showed an effect of treatment on body weight, with significant differences favoring quetiapine over risperidone and olanzapine. Simpson-Angus Scale scores were significantly worse with risperidone compared with both olanzapine and quetiapine at Week 3 and compared with quetiapine thereafter. Use of concomitant medications for anxiety or tension was significantly less frequent with quetiapine. In conclusion, quetiapine, risperidone, and olanzapine have similar efficacy in schizophrenia, but there are drug-specific differences for some AEs and in the use of concomitant medication that differentiate these agents.

Immediate and 8-month impact of a medical educational course for general practitioners on knowledge about schizophrenia and its treatment: results of a 3-phase study from Brescia, Italy.

OBJECTIVE: To test the efficacy of a training course on the diagnosis and treatment of schizophrenia, tailored for the general practitioner. METHOD: 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. RESULTS: 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). CONCLUSION: The teaching course on schizophrenia for general practitioners was effective, and the knowledge gained after teaching was stable across time.

Study on GRIA2, GRIA3 and GRIA4 genes highlights a positive association between schizophrenia and GRIA3 in female patients.

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.