The rapid antidepressant effectiveness of repeated dose of intravenous ketamine and intranasal esketamine: A post-hoc analysis of pooled real-world data.

INTRODUCTION: Intravenous ketamine (KET-IV) and intranasal esketamine (ESK-NS) are effective in the acute treatment of Treatment-Resistant Depression (TRD). Studies comparing KET-IV and ESK-NS concerning their action, safety, and tolerability are currently lacking. MATERIALS AND METHODS: We combined patients' data from two unipolar TRD cohorts that received KET-IV (n = 171) at the Canadian Rapid Treatment Center of Excellence in Toronto, Canada, or ESK-NS (n = 140) at several TRD clinics in Italy. The Quick Inventory for Depression Symptomatology-Self-Report-16/QIDS-SR16 in the KET-IV group and Montgomery-Åsberg Depression Rating Scale/MADRS in the ESK-NS group measured depressive symptoms at baseline (T0) and after the acute treatment phase (T1) (i.e., four infusions of KET-IV and eight administrations of ESK-NS). As different scales were used, the primary outcome was to compare the improvement in depression severity in the two cohorts by measuring effect sizes, response and remission rates. Finally, we compare side effects and discontinuation rates. RESULTS: At T1, KET-IV and ESK-NS significantly reduced depressive symptoms (respectively: QIDS-SR16 mean reduction = 5.65, p < 0.001; MADRS mean reduction = 11.41, p = 0.025). KET-IV showed larger effect sizes compared to ESK-NS (1.666 vs. 1.244). KET-IV had higher response rates (36 % vs. 25 %; p = 0.042) but not superior remission rates (13 % vs. 12 %; p = 0.845) than ESK-NS at T1. Despite more reported side effects, KET-IV did not cause more discontinuations for adverse events (4.6 % vs. 2.12 %; p = 0.228) than ESK-NS. CONCLUSION: KET-IV showed a higher short-term antidepressant effect, whereas ESK-NS exhibited lower side effects. Both were generally well tolerated. Future head-to-head studies should consider the long-term efficacy of these treatments.

Predicting outcome with Intranasal Esketamine treatment: A machine-learning, three-month study in Treatment-Resistant Depression (ESK-LEARNING).

Treatment-resistant depression (TRD) represents a severe clinical condition with high social and economic costs. Esketamine Nasal Spray (ESK-NS) has recently been approved for TRD by EMA and FDA, but data about predictors of response are still lacking. Thus, a tool that can predict the individual patients' probability of response to ESK-NS is needed. This study investigates sociodemographic and clinical features predicting responses to ESK-NS in TRD patients using machine learning techniques. In a retrospective, multicentric, real-world study involving 149 TRD subjects, psychometric data (Montgomery-Asberg-Depression-Rating-Scale/MADRS, Brief-Psychiatric-Rating-Scale/BPRS, Hamilton-Anxiety-Rating-Scale/HAM-A, Hamilton-Depression-Rating-Scale/HAMD-17) were collected at baseline and at one month/T1 and three months/T2 post-treatment initiation. We trained three different random forest classifiers, able to predict responses to ESK-NS with accuracies of 68.53% at T1 and 66.26% at T2 and remission at T2 with 68.60% of accuracy. Features like severe anhedonia, anxious distress, mixed symptoms as well as bipolarity were found to positively predict response and remission. At the same time, benzodiazepine usage and depression severity were linked to delayed responses. Despite some limitations (i.e., retrospective study, lack of biomarkers, lack of a correct interrater-reliability across the different centers), these findings suggest the potential of machine learning in personalized intervention for TRD.

Investigating the Effectiveness and Tolerability of Intranasal Esketamine Among Older Adults With Treatment-Resistant Depression (TRD): A Post-hoc Analysis from the REAL-ESK Study Group.

INTRODUCTION: Treatment-resistant depression (TRD) is a serious and debilitating psychiatric disorder that frequently affects older patients. Esketamine nasal spray (ESK-NS) has recently been approved as a treatment for TRD, with multiple studies establishing its efficacy and tolerability. However, the real-world effectiveness, tolerability, and safety of this treatment in older adults is still unclear. OBJECTIVES: To evaluate the efficacy and tolerability of ESK-NS in older subjects with TRD. METHODS: This is a post-hoc analysis of the REAL-ESK study, a multicenter, retrospective, observational study. Participants here selected were 65 years or older at baseline. The Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A) were used to assess depressive and anxiety symptoms, respectively. Data were collected at three-time points: baseline, 1 month after the start of treatment (T1), and 3 months after treatment (T2). RESULTS: The sample included older adults with TRD (n = 30). MADRS and HAM-A values decreased significantly at T1 (T0 versus T1: pholm <0.001, Cohen's d = 0.840) and T2 follow-ups (T0 versus T2: pholm <0.001, Cohen's d = 1.419). At T2, 53.3% of subjects were responders (MADRS score reduced ≥50%), while 33.33% were in remission (MADRS<10). ESK-NS-related adverse effects were in order of frequency dizziness (50%), followed by dissociation (33.3%), sedation (30%), and hypertension (13.33%). Six out of 30 participants (20%) discontinued treatment. CONCLUSIONS: Our findings provide preliminary evidence of ESK-NS effectiveness in older adults with TRD, a highly debilitating depressive presentation. Furthermore, we observe high levels of treatment-emergent adverse events, which, in the majority of instances, did not require treatment suspension.

Esketamine in treatment-resistant depression patients comorbid with substance-use disorder: A viewpoint on its safety and effectiveness in a subsample of patients from the REAL-ESK study.

Esketamine, the S-enantiomer of ketamine, has recently emerged as a therapy for treatment-resistant depression (TRD), showing both rapid antidepressant action and good efficacy and high safety. It is also indicated for the acute short-term treatment of psychiatric emergency due to major depressive disorder (MDD) and for depressive symptoms in adults with MDD with acute suicidal thoughts/behavior. We here provide preliminary insights on esketamine nasal spray (ESK-NS) effectiveness and safety among patients with a substance use disorder (SUD) within the sample of patients with TRD collected for the observational, retrospective, multicentre REAL-ESK study. Twenty-six subjects were retrospectively selected according to the presence of a SUD in comorbidity. Subjects enrolled completed the three different follow-up phases (T0/baseline, T1/after one month, and T2/after three months) and there were no dropouts. A decrease in Montgomery-Asberg depression rating scale (MADRS) scores was recorded, thus highlighting the antidepressant efficacy of ESK-NS (MADRS decreased from T0 to T1, t = 6.533, df=23, p<0.001, and from T1 to T2, t = 2.029, df=20, p = 0.056). Considering tolerability and safety issues, one or more side effects were reported by 19/26 subjects (73%) after treatment administration. All reported side effects were time-dependent and did not cause significant sequelae; among them, dissociative symptoms (38%) and sedation (26%) were the most frequently reported. Finally, no cases of abuse or misuse of ESK-NS were reported. Despite study limitations related to the inherent nature of the study, a limited number of patients, and a short follow-up period, ESK-NS showed to be effective and safe in patients diagnosed with TRD comorbid with a SUD.

Does social cognition change? Evidence after 4 years from the Italian Network for Research on Psychoses.

BACKGROUND: Deficits in social cognition (SC) are significantly related to community functioning in schizophrenia (SZ). Few studies investigated longitudinal changes in SC and its impact on recovery. In the present study, we aimed: (a) to estimate the magnitude and clinical significance of SC change in outpatients with stable SZ who were assessed at baseline and after 4 years, (b) to identify predictors of reliable and clinically significant change (RCSC), and (c) to determine whether changes in SC over 4 years predicted patient recovery at follow-up. METHODS: The reliable change index was used to estimate the proportion of true change in SC, not attributable to measurement error. Stepwise multiple logistic regression models were used to identify the predictors of RCSC in a SC domain (The Awareness of Social Inference Test [TASIT]) and the effect of change in TASIT on recovery at follow-up. RESULTS: In 548 participants, statistically significant improvements were found for the simple and paradoxical sarcasm of TASIT scale, and for the total score of section 2. The reliable change index was 9.8. A cut-off of 45 identified patients showing clinically significant change. Reliable change was achieved by 12.6% and RCSC by 8% of participants. Lower baseline TASIT sect. 2 score predicted reliable improvement on TASIT sect. 2. Improvement in TASIT sect. 2 scores predicted functional recovery, with a 10-point change predicting 40% increase in the probability of recovery. CONCLUSIONS: The RCSC index provides a conservative way to assess the improvement in the ability to grasp sarcasm in SZ, and is associated with recovery.

Treating bipolar depression with esketamine: Safety and effectiveness data from a naturalistic multicentric study on esketamine in bipolar versus unipolar treatment-resistant depression.

BACKGROUND: Bipolar depression accounts for most of the disease duration in type I and type II bipolar disorder (BD), with few treatment options, often poorly tolerated. Many individuals do not respond to first-line therapeutic options, resulting in treatment-resistant bipolar depression (B-TRD). Esketamine, the S-enantiomer of ketamine, has recently been approved for treatment-resistant depression (TRD), but no data are available on its use in B-TRD. OBJECTIVES: To compare the efficacy of esketamine in two samples of unipolar and bipolar TRD, providing preliminary indications of its effectiveness in B-TRD. Secondary outcomes included the evaluation of the safety and tolerability of esketamine in B-TRD, focusing on the average risk of an affective switch. METHODS: Thirty-five B-TRD subjects treated with esketamine nasal spray were enrolled and compared with 35 TRD patients. Anamnestic data and psychometric assessments (Montgomery-Asberg Depression Rating Scale/MADRS, Hamilton-depression scale/HAM-D, Hamilton-anxiety scale/HAM-A) were collected at baseline (T0), at one month (T1), and three months (T2) follow up. RESULTS: A significant reduction in depressive symptoms was found at T1 and T2 compared to T0, with no significant differences in response or remission rates between subjects with B-TRD and TRD. Esketamine showed a greater anxiolytic action in subjects with B-TRD than in those with TRD. Improvement in depressive symptoms was not associated with treatment-emergent affective switch. CONCLUSIONS: Our results supported the effectiveness and tolerability of esketamine in a real-world population of subjects with B-TRD. The low risk of manic switch in B-TRD patients confirmed the safety of this treatment.

Evolution of antipsychotic-induced extrapyramidal symptoms in patients with schizophrenia in the real-life: A 4-year follow-up naturalistic study.

Previous studies have shown, although not consistently, that first generation antipsychotics (FGA) are associated with a prevalence of extrapyramidal symptoms (EPS) higher than second generation antipsychotics (SGA). We assessed the prevalence and the incidence of antipsychotic-induced EPS in a large sample of community-dwelling Italian persons with schizophrenia before and after a 4-year naturalistic treatment, to shed light on their natural evolution and to identify possible predicting factors. EPS and psychopathology were assessed in 571 subjects with schizophrenia before (baseline) and after 4-year follow-up. Patients underwent treatment with SGA and/or FGA according to the referring clinicians' judgment. Relationships between EPS and psychopathology were assessed by network analysis, while a linear multiple regression investigated factors correlated to the presence of EPS at follow-up. EPS were significantly more frequent in the FGA- than in the SGA-treated group, and patients with EPS presented a more severe psychopathology. Parkinsonism was directly and positively connected with poor emotional expression at baseline and with poor emotional expression and disorganization at follow-up. Over the 4-year follow-up, emergent EPS were more frequent in FGA-treated patients, while relieved EPS occurred more frequently in SGA-treated persons. The presence of EPS at follow-up was significantly associated with EPS at baseline, illness duration, antipsychotic generation and the daily dose of antipsychotic medications. After a 4-year naturalistic treatment, EPS disappeared more frequently in SGA-treated patients, while they emerged more frequently in FGA-treated individuals. Therefore, although SGA did not eliminate the risk of EPS, these drugs seem to be associated to a more favorable EPS natural evolution.

Real-world experience of esketamine use to manage treatment-resistant depression: A multicentric study on safety and effectiveness (REAL-ESK study).

Background: Treatment-resistant Depression (TRD) represents a widespread disorder with significant direct and indirect healthcare costs. esketamine, the S-enantiomer of ketamine, has been recently approved for TRD, but real-world studies are needed to prove its efficacy in naturalistic settings. Objectives: Evaluate the effectiveness and safety of esketamine nasal spray in a clinical sample of patients with TRD from several Italian mental health services. Methods: REAL-ESK study is an observational, retrospective and multicentric study comprising a total of 116 TRD patients treated with esketamine nasal spray. Anamnestic data and psychometric assessment (MADRS, HAMD-21, HAM-A) were collected from medical records at baseline (T0), one month (T1) and three month (T2) follow-ups. Results: A significant reduction of depressive symptoms was found at T1 and T2 compared to T0. A dramatic increase in clinical response (64.2 %) and remission rates (40.6 %) was detected at T2 compared to T1. No unexpected safety concerns were observed, side effects rates were comparable to those reported in RCTs. No differences in efficacy have been found among patients with and without psychiatric comorbidities. Limitations: The open design of the study and the absence of a placebo or active comparator group are limitations. The study lacks an inter-rater reliability evaluation of the assessments among the different centres. Side effects evaluation did not involve any specific scale. Conclusions: Our findings support the safety and tolerability of esketamine in a real-world TRD sample. The later response and the non-inferiority in effectiveness in patients with comorbidities represent novel and interesting findings.

The Complex Interplay Between Physical Activity and Recovery Styles in Patients With Severe Mental Disorders in a Real-World Multicentric Study.

Compared with the general population, people with severe mental disorders have significantly worse physical health and a higher mortality rate, which is partially due to the adoption of unhealthy lifestyle behaviors, such as heavy smoking, use of alcohol or illicit drugs, unbalanced diet, and physical inactivity. These unhealthy behaviors may also play a significant role in the personal and functional recovery of patients with severe mental disorders, although this relationship has been rarely investigated in methodologically robust studies. In this paper, we aim to: a) describe the levels of physical activity and recovery style in a sample of patients with severe mental disorders; b) identify the clinical, social, and illness-related factors that predict the likelihood of patients performing physical activity. The global sample consists of 401 patients, with a main psychiatric diagnosis of bipolar disorder (43.4%, N = 174), psychosis spectrum disorder (29.7%; N = 119), or major depression (26.9%; N = 118). 29.4% (N = 119) of patients reported performing physical activity regularly, most frequently walking (52.1%, N = 62), going to the gym (21.8%, N = 26), and running (10.9%, N = 13). Only 15 patients (3.7%) performed at least 75 min of vigorous physical activity per week. 46.8% of patients adopted sealing over as a recovery style and 37.9% used a mixed style toward integration. Recovery style is influenced by gender (p < 0.05) and age (p < 0.05). The probability to practice regular physical activity is higher in patients with metabolic syndrome (Odds Ratio - OR: 2.1; Confidence Interval - CI 95%: 1.2-3.5; p < 0.050), and significantly lower in those with higher levels of anxiety/depressive symptoms (OR: 0.877; CI 95%: 0.771-0.998; p < 0.01). Globally, patients with severe mental disorders report low levels of physical activities, which are associated with poor recovery styles. Psychoeducational interventions aimed at increasing patients' motivation to adopt healthy lifestyle behaviors and modifying recovery styles may improve the physical health of people with severe mental disorders thus reducing the mortality rates.

Using combined environmental-clinical classification models to predict role functioning outcome in clinical high-risk states for psychosis and recent-onset depression.

BACKGROUND: Clinical high-risk states for psychosis (CHR) are associated with functional impairments and depressive disorders. A previous PRONIA study predicted social functioning in CHR and recent-onset depression (ROD) based on structural magnetic resonance imaging (sMRI) and clinical data. However, the combination of these domains did not lead to accurate role functioning prediction, calling for the investigation of additional risk dimensions. Role functioning may be more strongly associated with environmental adverse events than social functioning. AIMS: We aimed to predict role functioning in CHR, ROD and transdiagnostically, by adding environmental adverse events-related variables to clinical and sMRI data domains within the PRONIA sample. METHOD: Baseline clinical, environmental and sMRI data collected in 92 CHR and 95 ROD samples were trained to predict lower versus higher follow-up role functioning, using support vector classification and mixed k-fold/leave-site-out cross-validation. We built separate predictions for each domain, created multimodal predictions and validated them in independent cohorts (74 CHR, 66 ROD). RESULTS: Models combining clinical and environmental data predicted role outcome in discovery and replication samples of CHR (balanced accuracies: 65.4% and 67.7%, respectively), ROD (balanced accuracies: 58.9% and 62.5%, respectively), and transdiagnostically (balanced accuracies: 62.4% and 68.2%, respectively). The most reliable environmental features for role outcome prediction were adult environmental adjustment, childhood trauma in CHR and childhood environmental adjustment in ROD. CONCLUSIONS: Findings support the hypothesis that environmental variables inform role outcome prediction, highlight the existence of both transdiagnostic and syndrome-specific predictive environmental adverse events, and emphasise the importance of implementing real-world models by measuring multiple risk dimensions.

How to improve the physical health of people with severe mental illness? A multicentric randomized controlled trial on the efficacy of a lifestyle group intervention.

BACKGROUND: People with severe mental illnesses (SMI) have a mortality rate two times higher compared to the general population, with a decade of years of life lost. In this randomized controlled trial (RCT), we assessed in a sample of people with bipolar disorder, major depressive disorder, and schizophrenia spectrum disorder, the efficacy of an innovative psychosocial group intervention compared to a brief psychoeducational group intervention on patients' body mass index (BMI), body weight, waist circumference, Framingham and HOMA-IR indexes. METHODS: This is a multicentric RCT with blinded outcome assessments carried out in six Italian university centers. After recruitment patients were randomized to receive a 6-month psychosocial intervention to improve patients' physical health or a brief psychoeducational intervention. All recruited patients were assessed with standardized assessment instruments at baseline and after 6 months. Anthropometric parameters and blood samples have also been collected. RESULTS: Four-hundred and two patients with a diagnosis of bipolar disorder (43.3%), schizophrenia or other psychotic disorder (29.9%), or major depression (26.9%) were randomly allocated to the experimental (N = 206) or the control group (N = 195). After 6 months, patients from the experimental group reported a significant reduction in BMI (odds ratio [OR]: 1.93, 95% confidence intervals [CI]: 1.31-2.84; p < 0.001), body weight (OR = 4.78, 95% CI: 0.80-28.27, p < 0.05), and waist circumference (OR = 5.43, 95% CI: 1.45-20.30, p < 0.05). Participants with impaired cognitive and psychosocial functioning had a worse response to the intervention. CONCLUSIONS: The experimental group intervention was effective in improving the physical health in SMI patients. Further studies are needed to evaluate the feasibility of this intervention in real-world settings.

[Lifestyle in patients with severe mental disorders: a new target for psychosocial interventions?] / Stili di vita nei pazienti con disturbi mentali gravi: quali opportunità per il trattamento?

INTRODUCTION: Patients with severe mental disorders (namely schizophrenia, major depression and bipolar disorder) have a reduced life expectancy of at least 10 to 25 years compared with the general population. This mortality gap is due to the higher prevalence of comorbid physical disorders (such as diabetes, hypertension and cardiovascular diseases) in these patients compared to the general population. Factors contributing to the mortality gap include lack of access to primary care services, severity of clinical symptoms, internalized stigma and discrimination by healthcare professionals, pharmacological treatments and unhealthy lifestyle behaviours. Several international studies have highlighted the high prevalence of unhealthy lifestyle behaviours in patients with severe mental disorders, but a few data are available from Italian real-world settings. AIM: The present study aims to: 1) describe the lifestyle behaviours adopted by a sample of real-world patients affected by severe mental disorders; 2) identify differences in lifestyle behaviours according to diagnostic category. MATERIALS: The final sample consisted of 402 patients, mainly female (57%), with a mean age of 45.8±11.8 years. 35% of them suffers from moderate obesity and 40% of them is affected by hyperinsulinemia, hypercolestereloemia and hypertrygliceridemia. 70% of patients has sedentary behaviours. Moderate to severe nicotine dependence is reported by 42% of patients. Patients with bipolar disorders are more frequently smokers compared to other patients. No significant differences in lifestyle behaviours have been found among the three diagnostic groups. RESULTS AND CONCLUSIONS: Our data confirm that patients with severe mental disorders adopt unhealthy lifestyle behaviours, regardless their diagnosis. New psychosocial interventions, including motivational and psychoeducational components and targeting lifestyle behaviours, should be developed and disseminated in order to reduce the mortality gap.

The impact of clinical and social factors on the physical health of people with severe mental illness: Results from an Italian multicentre study.

Our manuscript aims to: 1) assess physical health in a sample of patients with severe mental disorders; and 2) identify the psychopathological and psychosocial characteristics associated with an increased likelihood of having a poor physical health. The study, funded by the Italian Ministry of Education, has been carried out in psychiatric outpatient units of six Italian University sites. All recruited patients have been assessed through standardized assessment instruments. Moreover, anthropometric parameters have been obtained at recruitment and a blood samples have been collected to assess cardiometabolic parameters. Four-hundred and two patients with a primary diagnosis of bipolar disorder (43.3%), schizophrenia or other psychotic disorder (29.9%), or major depression (26.9%) were recruited. Internalized stigma, psychosocial functioning, quality of life, psychiatric hospitalizations, depressive/anxiety and manic symptoms and cognition were those domains more strongly associated with poor metabolic parameters, including high body mass index, HOMA and Framingham indexes and waist circumference. There were no statistically significant differences among the three diagnostic groups. Our findings highlight the importance of perceived stigma and quality of life on patients' physical health. This should be taken into account when developing plans for reducing the mortality rate in patients with severe mental disorders.

Evidence of an interaction between FXR1 and GSK3ß polymorphisms on levels of Negative Symptoms of Schizophrenia and their response to antipsychotics.

BACKGROUND: Genome-Wide Association Studies (GWASs) have identified several genes associated with Schizophrenia (SCZ) and exponentially increased knowledge on the genetic basis of the disease. In addition, products of GWAS genes interact with neuronal factors coded by genes lacking association, such that this interaction may confer risk for specific phenotypes of this brain disorder. In this regard, fragile X mental retardation syndrome-related 1 (FXR1) gene has been GWAS associated with SCZ. FXR1 protein is regulated by glycogen synthase kinase-3ß (GSK3ß), which has been implicated in pathophysiology of SCZ and response to antipsychotics (APs). rs496250 and rs12630592, two eQTLs (Expression Quantitative Trait Loci) of FXR1 and GSK3ß, respectively, interact on emotion stability and amygdala/prefrontal cortex activity during emotion processing. These two phenotypes are associated with Negative Symptoms (NSs) of SCZ suggesting that the interaction between these SNPs may also affect NS severity and responsiveness to medication. METHODS: To test this hypothesis, in two independent samples of patients with SCZ, we investigated rs496250 by rs12630592 interaction on NS severity and response to APs. We also tested a putative link between APs administration and FXR1 expression, as already reported for GSK3ß expression. RESULTS: We found that rs496250 and rs12630592 interact on NS severity. We also found evidence suggesting interaction of these polymorphisms also on response to APs. This interaction was not present when looking at positive and general psychopathology scores. Furthermore, chronic olanzapine administration led to a reduction of FXR1 expression in mouse frontal cortex. DISCUSSION: Our findings suggest that, like GSK3ß, FXR1 is affected by APs while shedding new light on the role of the FXR1/GSK3ß pathway for NSs of SCZ.

Machine learning-based ability to classify psychosis and early stages of disease through parenting and attachment-related variables is associated with social cognition.

BACKGROUND: Recent views posited that negative parenting and attachment insecurity can be considered as general environmental factors of vulnerability for psychosis, specifically for individuals diagnosed with psychosis (PSY). Furthermore, evidence highlighted a tight relationship between attachment style and social cognition abilities, a key PSY behavioral phenotype. The aim of this study is to generate a machine learning algorithm based on the perceived quality of parenting and attachment style-related features to discriminate between PSY and healthy controls (HC) and to investigate its ability to track PSY early stages and risk conditions, as well as its association with social cognition performance. METHODS: Perceived maternal and paternal parenting, as well as attachment anxiety and avoidance scores, were trained to separate 71 HC from 34 PSY (20 individuals diagnosed with schizophrenia + 14 diagnosed with bipolar disorder with psychotic manifestations) using support vector classification and repeated nested cross-validation. We then validated this model on independent datasets including individuals at the early stages of disease (ESD, i.e. first episode of psychosis or depression, or at-risk mental state for psychosis) and with familial high risk for PSY (FHR, i.e. having a first-degree relative suffering from psychosis). Then, we performed factorial analyses to test the group x classification rate interaction on emotion perception, social inference and managing of emotions abilities. RESULTS: The perceived parenting and attachment-based machine learning model discriminated PSY from HC with a Balanced Accuracy (BAC) of 72.2%. Slightly lower classification performance was measured in the ESD sample (HC-ESD BAC = 63.5%), while the model could not discriminate between FHR and HC (BAC = 44.2%). We observed a significant group x classification interaction in PSY and HC from the discovery sample on emotion perception and on the ability to manage emotions (both p = 0.02). The interaction on managing of emotion abilities was replicated in the ESD and HC validation sample (p = 0.03). CONCLUSION: Our results suggest that parenting and attachment-related variables bear significant classification power when applied to both PSY and its early stages and are associated with variability in emotion processing. These variables could therefore be useful in psychosis early recognition programs aimed at softening the psychosis-associated disability.

Accuracy of self-assessment of real-life functioning in schizophrenia.

A consensus has not yet been reached regarding the accuracy of people with schizophrenia in self-reporting their real-life functioning. In a large (n = 618) cohort of stable, community-dwelling schizophrenia patients we sought to: (1) examine the concordance of patients' reports of their real-life functioning with the reports of their key caregiver; (2) identify which patient characteristics are associated to the differences between patients and informants. Patient-caregiver concordance of the ratings in three Specific Level of Functioning Scale (SLOF) domains (interpersonal relationships, everyday life skills, work skills) was evaluated with matched-pair t tests, the Lin's concordance correlation, Somers' D, and Bland-Altman plots with limits of agreement (LOA). Predictors of the patient-caregiver differences in SLOF ratings were assessed with a linear regression with multivariable fractional polynomials. Patients' self-evaluation of functioning was higher than caregivers' in all the evaluated domains of the SLOF and 17.6% of the patients exceeded the LOA, thus providing a self-evaluation discordant from their key caregivers. The strongest predictors of patient-caregiver discrepancies were caregivers' ratings in each SLOF domain. In clinically stable outpatients with a moderate degree of functional impairment, self-evaluation with the SLOF scale can become a useful, informative and reliable clinical tool to design a tailored rehabilitation program.

Assessment of de novo copy-number variations in Italian patients with schizophrenia: Detection of putative mutations involving regulatory enhancer elements.

OBJECTIVES: Variants appearing de novo in genes regulating key neurodevelopmental processes and/or in non-coding cis-regulatory elements (CREs), as enhancers, may increase the risk for schizophrenia. However, CREs involvement in schizophrenia needs to be explored more deeply. METHODS: We investigated de novo copy-number variations (CNVs) in the whole-genomic DNA obtained from 46 family trios of schizophrenia probands by using the Enhancer Chip, a customised array CGH able to investigate the whole genome with a 300-kb resolution, specific disease loci at a ten-fold higher resolution, and which was highly enriched in probes in more than 1,250 enhancer elements selected from Vista Enhancer Browser. RESULTS: In seven patients, we found de novo CNVs, two of which overlapped VISTA enhancer elements. De novo CNVs encompass genes (CNTNAP2, MAGI1, TSPAN7 and MET) involved in brain development, while that involving the enhancer element hs1043, also includes ZIC1, which plays a role in neural development and is responsible of behavioural abnormalities in Zic mutant mice. CONCLUSIONS: These findings provide further evidence for the involvement of de novo CNVs in the pathogenesis of schizophrenia and suggest that CNVs affecting regulatory enhancer elements could contribute to the genetic vulnerability to the disorder.

Grey matter volume patterns in thalamic nuclei are associated with familial risk for schizophrenia.

Previous evidence suggests reduced thalamic grey matter volume (GMV) in patients with schizophrenia (SCZ). However, it is not considered an intermediate phenotype for schizophrenia, possibly because previous studies did not assess the contribution of individual thalamic nuclei and employed univariate statistics. Here, we hypothesized that multivariate statistics would reveal an association of GMV in different thalamic nuclei with familial risk for schizophrenia. We also hypothesized that accounting for the heterogeneity of thalamic GMV in healthy controls would improve the detection of subjects at familial risk for the disorder. We acquired MRI scans for 96 clinically stable SCZ, 55 non-affected siblings of patients with schizophrenia (SIB), and 249 HC. The thalamus was parceled into seven regions of interest (ROIs). After a canonical univariate analysis, we used GMV estimates of thalamic ROIs, together with total thalamic GMV and premorbid intelligence, as features in Random Forests to classify HC, SIB, and SCZ. Then, we computed a Misclassification Index for each individual and tested the improvement in SIB detection after excluding a subsample of HC misclassified as patients. Random Forests discriminated SCZ from HC (accuracy=81%) and SIB from HC (accuracy=75%). Left anteromedial thalamic volumes were significantly associated with both multivariate classifications (p<0.05). Excluding HC misclassified as SCZ improved greatly HC vs. SIB classification (Cohen's d=1.39). These findings suggest that multivariate statistics identify a familial background associated with thalamic GMV reduction in SCZ. They also suggest the relevance of inter-individual variability of GMV patterns for the discrimination of individuals at familial risk for the disorder.

The relationships of personal resources with symptom severity and psychosocial functioning in persons with schizophrenia: results from the Italian Network for Research on Psychoses study.

The relationships of personal resources with symptom severity and psychosocial functioning have never been tested systematically in a large sample of people with schizophrenia. We applied structural equation models to a sample of 921 patients with schizophrenia collected in a nationwide Italian study, with the aim to identify, among a large set of personal resources, those that may have an association with symptom severity or psychosocial functioning. Several relevant demographic and clinical variables were considered concurrently. Poor service engagement and poor recovery style, as well as older age and younger age at onset, were related to greater symptom severity and poorer social functioning. Higher resilience and higher education were related to better social functioning only. Poor problem-focused coping and internalized stigma, as well as male gender and depression, were related to symptom severity only. The explored variables showed distinctive and partially independent associations with symptom severity and psychosocial functioning. A deeper understanding of these relationships may inform treatment decisions.

Converging evidence for the association of functional genetic variation in the serotonin receptor 2a gene with prefrontal function and olanzapine treatment.

IMPORTANCE: Serotonin (5-hydroxytryptamine) receptor 2a (5-HT2AR) signaling is important for modulation of corticostriatal pathways and prefrontal activity during cognition. Furthermore, newer antipsychotic drugs target 5-HT2AR. A single-nucleotide polymorphism in the 5-HT2AR gene (HTR2A rs6314, C>T; OMIM 182135) has been weakly associated with differential 5-HT2AR signaling and with physiologic as well as behavioral effects. OBJECTIVE: To use a hierarchical approach to determine the functional effects of this single-nucleotide polymorphism on 5-HT2AR messenger RNA and protein expression, on prefrontal phenotypes linked with genetic risk for schizophrenia, and on treatment with olanzapine. DESIGN: In silico predictions, in vitro, and case-control investigations. SETTING: Academic and clinical facilities. PARTICIPANTS: The postmortem study included 112 brains from healthy individuals; the in vivo investigation included a total sample of 371 healthy individuals and patients with schizophrenia. EXPOSURES Patients received olanzapine monotherapy for 8 weeks. MAIN OUTCOMES AND MEASURES: In silico predictions, messenger RNA, and protein expression in postmortem human prefrontal cortex and HeLa cells, functional magnetic resonance imaging prefrontal activity and behavior during working memory and attention in healthy individuals, and response to an 8-week trial of olanzapine treatment in patients with schizophrenia. RESULTS: Bioinformatic analysis predicted that rs6314 alters patterns of splicing, with possible effects on HTR2A expression. Moreover, the T allele was associated with reduced prefrontal messenger RNA expression in postmortem prefrontal cortex, with reduced protein expression in vitro, inefficient prefrontal blood oxygen level-dependent functional magnetic resonance imaging response during working memory and attentional control processing, and impaired working memory and attention behavior, as well as with attenuated improvement in negative symptoms after olanzapine treatment. CONCLUSIONS AND RELEVANCE: Our results suggest that HTR2A rs6314 affects 5-HT2AR expression and functionally contributes to genetic modulation of known endophenotypes of schizophrenia-like higher-level cognitive behaviors and related prefrontal activity, as well as response to treatment with olanzapine.