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Abstract Background One third to two thirds of people with schizophrenia have persistent psychotic symptoms despite clozapine treatment. Under real-world circumstances, the need to provide effective therapeutic interventions to patients who do not have an optimal response to clozapine has been cited as the most common reason for simultaneously prescribing a second antipsychotic drug in combination treatment strategies. In a clinical area where the pressing need of providing therapeutic answers has progressively increased the occurrence of antipsychotic polypharmacy, despite the lack of robust evidence of its efficacy, we sought to implement a pre-planned protocol where two alternative therapeutic answers are systematically provided and evaluated within the context of a pragmatic, multicentre, independent randomised study. Methods/Design The principal clinical question to be answered by the present project is the relative efficacy and tolerability of combination treatment with clozapine plus aripiprazole compared with combination treatment with clozapine plus haloperidol in patients with an incomplete response to treatment with clozapine over an appropriate period of time. This project is a prospective, multicentre, randomized, parallel-group, superiority trial that follow patients over a period of 12 months. Withdrawal from allocated treatment within 3 months is the primary outcome. Discussion The implementation of the protocol presented here shows that it is possible to create a network of community psychiatric services that accept the idea of using their everyday clinical practice to produce randomised knowledge. The employed pragmatic attitude allowed to randomly allocate more than 100 individuals, which means that this study is the largest antipsychotic combination trial conducted so far in Western countries. We expect that the current project, by generating evidence on whether it is clinically useful to combine clozapine with aripiprazole rather than with haloperidol, provides physicians with a solid evidence base to be directly applied in the routine care of patients with schizophrenia. Trial Registration Clincaltrials.gov Identifier: NCT00395915

Aims: The current range of labeling terms-at-risk mental state (ARMS), ultra-high risk for psychosis (UHR), and attenuated psychotic syndrome (APS)-used to refer to the psychosis-risk concept is varied, and their acceptability and potential stigma are not well understood. By involving Italian youth with lived experience of mental ill-health, we aimed to generate new labeling terms for psychosis-risk, and to evaluate literacy, attitudes, and preferences regarding these and the existing terms. Additionally, we investigated opinions of disclosure of the at-risk concept in clinical practice., Methods: Through a dual-moderator focus group, novel diagnostic terms were coined for the at-risk concept: psychosis proneness (PP), change of personal reality (CPR), and hints of subjectivity dysregulation (HSD). A specifically designed questionnaire was then completed by 47 help-seeking youths, 60 relatives, and 61 clinicians to test newly generated and already established at-risk terms., Results: Literacy on already established terms was significantly lower among youth (mean= 42 %) and relatives (mean= 38 %). ARMS was the preferred and least stigmatizing term among young people and clinicians. UHR was considered the most stigmatizing label. Among newly generated terms, CPR was the least stigmatizing and most informative. Disclosure of at-risk terminology was generally preferred after establishing a trusting clinician-patient relationship., Conclusions: Findings support ARMS as a useful and acceptable term in clinical practice with young people, while UHR is associated with the highest stigma. CPR is promising and should be tested in cross-cultural studies. In Italy, there is an urgent need for improving literacy on prevention in mental health., Competing Interests: Declaration of Competing Interest I have nothing to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Research on the relationship between personality and psychosis onset is growing, with the goal of preventing or intervening early in patients' vulnerability. The identification of individuals with at-risk mental states has enabled the development of early intervention strategies, such as Programma 2000, a youth mental health service that was implemented in Milan (Italy)., Aims: Focusing on the 18-25 age range-the time window with the highest incidence of psychotic onset-this study aims to identify the personality traits that may characterize the at-risk mental states and the social functioning of a group of help-seeking young adults., Methods: The sample includes 169 people (48.5% males and 51.5% females). Data were collected during an initial assessment that comprised the Social and Occupational Functioning Assessment Scale, the Personality Inventory for DSM-5, the Checklist ERIraos and a clinical session., Results: Results identified a three-cluster solution based on the Checklist scores: Cluster 1 'Not at psychotic risk'; Cluster 2 'At intermediate risk'; Cluster 3 'With psychotic onset'. The multivariate analysis of the variance of personality traits shows significant differences among the clusters in negative affect, detachment and disinhibition. Higher scores in these traits may distinguish individuals, not at psychotic risk from those at intermediate risk or with psychotic onset. Moreover, social functioning was found to be negatively associated with clusters of psychotic risk., Conclusion: Findings from this study highlighted the need to evaluate personalized interventions targeting such personality traits that could prevent psychotic transition and promote psychological well-being., (© 2023 The Authors. Early Intervention in Psychiatry published by John Wiley & Sons Australia, Ltd.)

Introduction: Different studies confirm a stronger link between maladaptive personality traits and Non-suicidal Self-injury (NSSI). Additionally, the interest in the relationship between the experience of the COVID-19 pandemic and NSSI is growing. The present study aims (a) to investigate differences in personality traits between individuals with NSSI, suicidal ideation, NSSI and suicidal ideation co-occurrence and none; (b) to observe which personality traits predominantly influence the occurrence of self-harm acts; (c) to evaluate the difference in self-harm attitudes pre and post COVID-19 pandemic., Method: 270 (108 males and 162 females) participants aged between 18 and 25 were included in the study. Everyone participated in a clinical interview and completed an assessment consisting of the Personality Inventory for DSM-5 (PID-5) and the Health of the Nation Outcome Scales (HoNOS). A multivariate analysis of variance (MANOVA), a multiple hierarchical regression analysis, controlling for age and gender and a T-test for independent samples were conducted., Results: The individuals with the highest levels of negative affectivity, detachment, antagonism, and psychoticism are those who simultaneously present suicidal ideation and NSSI. Moreover, age and detachment predicted higher scores in self-harm attitudes. Our results unexpectedly do not confirm an upward trend of NSSI and suicidal ideation during the pandemic period., Limitations: The study is cross-sectional, and no causal links can be assumed; the groups involved were not homogeneous for numerosity., Conclusions: The results testify that the study of maladaptive traits is fundamental to a greater understanding of NSSIs. Working clinically on those could potentially reduce., Competing Interests: The authors declare they do not have any conflict of interest., (© 2023 The Authors. Published by Elsevier B.V.)

Background: Defective insight is a hallmark of schizophrenia. Less is known about insight in emerging psychosis. In this study a widely used measure of cognitive insight, the Beck Cognitive Insight Scale (BCIS), has been applied to a sample including patients with first-episode psychosis (FEP), at ultra-high risk (UHR) for psychosis, and help-seeking youths without psychotic symptoms., Methods: The Comprehensive Assessment of At-Risk Mental State (CAARMS) interview was used to classify patients. Enrolled patients were assessed with the General Health Questionnaire-12 (GHQ-12), the Prodromal Questionnaire-16 (PQ-16), the Social and Occupational Functioning Assessment Scale (SOFAS), and the BCIS., Results: The sample included 212 participants (58%) with non-psychotic mental distress, 131 participants (36%) were UHR, and 22 (6%) were with FEP. Males and females were in equal proportion, mean age was 19.2 ± 2.6 years old (range: 15-25 years). Reliability (Cronbach's alpha) was good for clinical scales (>0.7) and acceptable (around 0.6) for the two BCIS subscales. The self-certainty subscale of the BCIS was more reproducible in factor analysis than the self-reflectiveness scale. Youths devoid of psychotic symptoms scored lower than UHR and FEP participants on the GHQ-12 and the PQ-16 and had better psychosocial functioning as measured by the SOFAS. Levels of cognitive insight did not differ between groups., Conclusion: People in the early stages of psychosis may be still accessible to self-reflectiveness and more hesitant about the certainty of their beliefs than patients at more advanced stages of the illness, as those with fully displayed schizophrenia., (Copyright © 2022. Published by Elsevier B.V.)

Background: Ultra-high risk (UHR) people are a heterogeneous group with variable outcomes. This study aimed at (a) estimating trajectories of response to treatment to identify homogeneous subgroups; (b) establishing the impact on these trajectories of known predictors of outcome in UHR subjects., Methods: Mixed models of growth curves and latent class growth analysis (LCGA) were applied to the 24-item brief psychiatric rating scale (BPRS) to measure the response to treatment over 2 years in 125 UHR participants. Group differences were tested on sociodemographic variables and clinical indicators that are known to affect the outcome in UHR people., Results: BPRS scores decreased across all tested models, with a greater decrease for affective and positive symptoms than for all other dimensions of BPRS. Past admissions to the hospital for psychiatric reasons other than psychosis and the presence of a decline in premorbid functioning before the episode were associated with a slower decrease of BPRS score. LCGA identified three classes, one (82% of participants) with a progressive decrease in the BPRS scores, a second class with a moderate improvement (10%), and a third with no improvement (8%). Those in the 'no improvement' class had a higher chance of receiving a diagnosis of psychosis within the spectrum of schizophrenia., Conclusion: Most UHR individuals that are treated within a specialized service undergo substantial improvement in their psychopathology, but some seem resistant to the protocol of treatment and need close reevaluation within the first 12 months of treatment., (© 2021 The Authors. Early Intervention in Psychiatry published by John Wiley & Sons Australia, Ltd.)

Background: The prescription of antipsychotics outside overt psychotic conditions remains controversial, especially in youth where it is relatively widespread. Furthermore, some studies seem to indicate that antipsychotic exposure in individuals at ultra-high-risk (UHR) for psychosis is associated with higher conversion rates. This study was set up to test whether the inter-current prescription of antipsychotics in UHR patients was related to the psychometric threshold for a diagnosis of psychosis., Methods: The 24-item Brief Psychiatric Rating Scale (BPRS) was used to quantify treatment response up to 2 years in 125 UHR participants. Standard psychometric criteria were used to quantify conversion to psychosis. Kaplan-Mayer and Cox proportional hazard survival analysis were applied to determine the impact of having or not received the prescription of an antipsychotic drug., Results: Over the study period 30 (24%) subjects received the prescription of an antipsychotic. In the sample, there were 31 participants (25%) who had reached the psychometric threshold for conversion to psychosis after 2 years of treatment. UHR people who received a prescription of antipsychotics during the first 2 years of treatment were statistically more likely to reach the psychometric threshold for conversion to psychosis on the BPRS: Hazard ratio = 3.03 (95%CI: 1.49-6.16); p = .003., Conclusion: This finding supports the hypothesis that the prescription of antipsychotics within UHR cohorts is to be considered a red flag for higher incipient risk of conversion to psychosis., (© 2021 The Authors. Early Intervention in Psychiatry published by John Wiley & Sons Australia, Ltd.)

The diagnosis of psychosis is a challenge for the scientific community, both in terms of its definition and treatment. Some recent studies have investigated the relationship between personality and psychosis onset to prevent or intervene early. Sixty young adults were recruited during their first access in 2019 near the Community Mental Health Service of Niguarda Hospital, Milan, Italy. The assessment included the Social and Occupational Functioning Assessment Scale (SOFAS), the Global Assessment of Functioning (GAF) (clinician scales), the 16-item Version of the Prodromal Questionnaire (PQ-16), the Personality Inventory for DSM-5 (PID-5) (self-report), and a clinical session. Statistical analysis was performed by SPSS. The results show a negative correlation between the Detachment domain and the GAF scores. Correlational analysis also highlights that all PID-5 domains, except for Antagonism, have positive correlations with high scores in the PQ-16. The multivariate analysis of variance showed that patients diagnosed with versus without a psychotic disorder significantly differed on Detachment, Antagonism and Psychoticism PID-5 domains. The involvement of the personality construct in psychopathological development is displayed. In particular, higher levels of Detachment and Psychoticism can distinguish people who are more vulnerable to psychosis or who already have overt psychosis from those who do not have a psychotic predisposition. The study highlights the fundamental role of personality traits, emerging from PID-5, to distinguish young adults at risk of onset.

Objective: Preliminary evidence suggested that sertraline might be slightly superior to other antidepressant medications in terms of efficacy. The aim of this study was to carry out a systematic review and meta-analysis to compare sertraline with any other antidepressant in the acute phase treatment of major depression at 8 weeks., Data Sources: MEDLINE; EMBASE; the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register; and the Cochrane Central Register of Controlled Trials up to August 2007. No language restriction. The following search strategy was used: diagnosis = depress* or dysthymi* or adjustment disorder* or mood disorder* or affective disorder or affective symptoms, and intervention (or free text) = sertraline. Reference lists of relevant papers and previous systematic reviews were hand-searched. Pharmaceutical companies and experts in this field were contacted for supplemental data., Study Selection: Only randomized controlled trials allocating patients with major depression to sertraline versus any other antidepressant agent., Data Extraction: Three reviewers independently extracted data. A double-entry procedure was employed by 2 reviewers. To analyze data, a very conservative approach with a 99% confidence interval (CI) and a random effects model was used. Information extracted included study characteristics, participant characteristics, intervention details, and outcome measures, such as the number of patients who responded to treatment and the number of patients who failed to complete the study by any cause at 8 weeks., Data Synthesis: This systematic review and meta-analysis found that sertraline is statistically significantly better than fluoxetine (relative risk [RR] = 0.85, 99% CI = 0.74 to 0.98; number needed to treat [NNT] = 12) and other SSRIs as a class (RR = 0.88, 99% CI = 0.78 to 0.99; NNT = 17) and highlighted a consistent even though not statistically significant trend in favor of sertraline over many other antidepressants both in terms of efficacy and acceptability in a homogeneous and clinically relevant time frame of 8 weeks., Conclusions: The results of this review suggest that sertraline may be a candidate as the initial choice of antidepressant for people with major depression., (Copyright 2008 Physicians Postgraduate Press, Inc.)

In the field of meta-analyses of antidepressant randomized controlled trials (RCTs), it is unclear whether a relationship exists between study quality, treatment estimates, and different quality measures. In this systematic review, we investigated whether quality of RCTs allocating patients with major depression to fluoxetine versus any other antidepressant agent influenced treatment estimates. We designed a systematic review and meta-regression analysis of RCTs, obtaining data from the Cochrane Collaboration Depressive Anxiety and Neurosis Controlled Trials Register, Cochrane Controlled Trials Register, MEDLINE, EMBASE, reference lists, and specialist textbooks, with no language restriction. Two reviewers independently extracted data. Efficacy and tolerability outcomes were calculated for the overall sample and for the subgroup of high-quality trials. Quality was assessed using the Jadad scale, the Cochrane Collaboration Depressive Anxiety and Neurosis quality assessment instrument and 3 items of the CONSORT statement. A meta-regression analysis was also carried out. Thirty-nine RCTs contributed to efficacy and 74 to tolerability analyses. We found no correlation between the methodological quality of reports of RCTs and treatment estimates of efficacy and tolerability. Subgroup analyses of high-quality trials provided treatment estimates that did not materially change from overall estimates. This finding was further confirmed by the meta-regression analysis. Quality is an important issue and meta-analyses should take quality into consideration to provide less biased treatment estimates. However, current quality measures are not related with treatment estimates in antidepressant trials and may not be useful weighting tools when meta-analyses of data extracted from antidepressant RCTs are carried out.

Objective: To assess whether the impact factor, a measure of the frequency with which journal articles are cited in the scientific literature, is a proxy measure of the quality of articles reporting the results of randomized controlled trials., Method: The quality of trials included in an ongoing Cochrane review concerned with the antidepressant fluoxetine was assessed using the Cochrane Collaboration Depression, Anxiety, and Neurosis quality assessment instrument, the Jadad scale, and the quality criterion of the Cochrane Collaboration Handbook. Journal impact factors were extracted from the Journal Citation Report., Results: A total of 131 articles reported results from 132 clinical trials comparing fluoxetine with other antidepressants. The relationship between trial quality and the impact factor of journals where these studies were published, stratified by period of publication, revealed that journals with impact factors above 4 points published only trials with above-average overall quality ratings, while journals with impact factors below 4 points published both high- and low-quality trials. The Jadad scale revealed similar quality in trials published in journals with high, medium, and low impact factors (Pearson chi(2) = 0.298, p = .861), and the quality criterion of the Cochrane Collaboration Handbook showed unclear randomization in the majority of trials and in all 15 trials published in high-impact factor journals (Pearson chi(2) = 4.678, p = .096)., Conclusion: The impact factor of journals is not a valid measure of randomized controlled trial quality.

Background: Depression is common in primary care and it is associated with marked personal, social and economic morbidity, and creates significant demands on service providers in terms of workload. Treatment is predominantly pharmaceutical or psychological. Fluoxetine, the first of a group of antidepressant (AD) agents known as selective serotonin reuptake inhibitors (SSRIs), has been studied in many randomised controlled trials (RCTs) in comparison with tricyclic (TCA), heterocyclic and related ADs, and other SSRIs. These comparative studies provided contrasting findings. In addition, systematic reviews of RCTs have always considered the SSRIs as a group, and evidence applicable to this group of drugs might not be applicable to fluoxetine alone. The present systematic review assessed the efficacy and tolerability profile of fluoxetine in comparison with TCAs, SSRIs and newer agents., Objectives: To determine the efficacy of fluoxetine, compared with other ADs, in alleviating the acute symptoms of depression, and to review its acceptability., Search Strategy: Relevant studies were located by searching the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR), the Cochrane Central Register of Controlled Trials (CENTRAL), Medline (1966-2004) and Embase (1974-2004). Non-English language articles were included., Selection Criteria: Only RCTs were included. For trials which have a crossover design only results from the first randomisation period were considered., Data Collection and Analysis: Data were independently extracted by two reviewers using a standard form. Responders to treatment were calculated on an intention-to-treat basis: drop-outs were always included in this analysis. When data on drop-outs were carried forward and included in the efficacy evaluation, they were analysed according to the primary studies; when dropouts were excluded from any assessment in the primary studies, they were considered as treatment failures. Scores from continuous outcomes were analysed including patients with a final assessment or with the last observation carried forward. Tolerability data were analysed by calculating the proportion of patients who failed to complete the study and who experienced adverse reactions out of the total number of randomised patients. The primary analyses used a fixed effects approach, and presented Peto Odds Ratio (PetoOR) and Standardised Mean Difference (SMD)., Main Results: On a dichotomous outcome fluoxetine was less effective than dothiepin (PetoOR: 2.09, 95% CI 1.08 to 4.05), sertraline (PetoOR: 1.40, 95% CI 1.11 to 1.76), mirtazapine (PetoOR: 1.64, 95% CI 1.01 to 2.65) and venlafaxine (Peto OR: 1.40, 95% CI 1.15 to 1.70). On a continuous outcome, fluoxetine was more effective than ABT-200 (Standardised Mean Difference (SMD) random effects: - 1.85, 95% CI - 2.25 to - 1.45) and milnacipran (SMD random effects: - 0.38, 95% CI - 0.71 to - 0.06); conversely, it was less effective than venlafaxine (SMD random effect: 0.11, 95% CI 0.00 to 0.23), however these figures were of borderline statistical significance. Fluoxetine was better tolerated than TCAs considered as a group (PetoOR: 0.78, 95% CI 0.68 to 0.89), and was better tolerated in comparison with individual ADs, in particular than amitriptyline (PetoOR: 0.64, 95% CI 0.47 to 0.85) and imipramine (PetoOR: 0.79, 95% CI 0.63 to 0.99), and among newer ADs than ABT-200 (PetoOR: 0.21, 95% CI 0.10 to 0.41), pramipexole (PetoOR: 0.20, 95% CI 0.08 to 0.47) and reboxetine (PetoOR: 0.61, 95% CI 0.40 to 0.94)., Authors' Conclusions: There are statistically significant differences in terms of efficacy and tolerability between fluoxetine and certain ADs, but the clinical meaning of these differences is uncertain, and no definitive implications for clinical practice can be drawn. From a clinical point of view the analysis of antidepressants' safety profile (adverse effect and suicide risk) remains of crucial importance and more reliable data about these outcomes are needed. Waiting for more robust evidence, treatment decisions should be based on considerations of clinical history, drug toxicity, patient acceptability, and cost. We need for large, pragmatic trials, enrolling heterogeneous populations of patients with depression to generate clinically relevant information on the benefits and harms of competitive pharmacological options. A meta-analysis of individual patient data from the randomised trials is clearly necessary.

Maintenance treatment for depression should be considered as a chronic disease management programme. Several studies have reported that sertraline (SRT) can be useful in preventing relapses and recurrent episodes of major depression.Twenty-three outpatients, 14 males and 9 females, affected by major depressive disorder, recurrent (DSM-IV criteria) were included. The patients were prescribed 25-150 mg of SRT for 12 months and were evaluated at baseline (T(0)), after 15 days (T(0.5)), 30 days (T(1)), 6 months (T(6)) and 12 months (T(12)) by using the brief psychiatric rating scale (BPRS), Hamilton rating scale for anxiety (HRS-A) and Hamilton rating scale for depression (HRS-D). Plasma samples for SRT level determination were collected at T(0.5), T(1), T(6) and T(12). There was a positive relationship between SRT oral dose and drug plasma levels. Lower plasma levels, 25-50 ng/ml, were adequate for clinical maintenance treatment. Our data suggest that SRT seems to be effective and well tolerated at low dosages both in the acute and maintenance treatment of recurrent depression. Monitoring the SRT plasma level, even though not strictly necessary from a clinical point of view, can be useful in optimizing treatment., (Copyright 2003 John Wiley & Sons, Ltd.)

This study evaluated the efficacy of nutritional management with and without fluoxetine (FLX) in anorexia nervosa diagnosed according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. Twenty-one patients, with a mean body mass index (BMI) of 15.21+/-2.33 kg/m(2), were treated with nutritional management and FLX at a mean dosage of 30.00+/-9.35 mg (pharmacological group); seventy-four patients, with a mean BMI of 14.24+/-2.16 kg/m(2), were treated only with nutritional management (nutritional group). Clinical evaluation was carried out under single-blind conditions at basal time and after 3, 6, and 12 months by a structured clinical interview, the Eating Disorder Interview based on Longitudinal Interval Follow-Up Evaluation (EDI-LIFE) and using a self-reported questionnaire, the Eating Disorder Inventory (EDI). BMI significantly increased in both the two treatment groups. In addition, the increase shown by the pharmacological group appeared near the beginning of treatment (i.e., at T1) and it was significantly higher than the increase shown by the nutritional group. Physical exercise showed a significant decrease in the pharmacological treatment group. On the other hand, fear of fatness and the scores of the subscales of the EDI significantly decreased in the nutritional treatment group. In terms of weight, the pharmacological group presented the higher amount of therapeutic success.

Sertraline (SRT) has been shown to be an effective antidepressant in extensive clinical trial programs but data on plasma concentrations regarding clinical outcome and tolerability are lacking. Twenty-one out-patients of both sexes, with mean age of 50.23 years (S.D. = 17.37), affected by major depressive disorder, recurrent (Diagnostic and Statistical Manual of Mental Disorder--IV, DSM-IV), were treated with 25-150 mg of SRT once a day (mean=66.26 mg, S.D.=30.50) for 30 days. Clinical evaluation was assessed at baseline (T0), after 15 days (T15), and then after 30 days (T30). Plasma samples for SRT level determination were collected at T30. Brief Psychiatric Rating Scale (BPRS), Hamilton Rating Scale for Depression (HRS-D), and Hamilton Rating Scale for Anxiety (HRS-A) showed a significant improvement during the study (P<.01 vs. T0). The most commonly reported side effects were nausea (19%), cephalalgia (9.5%), dry mouth (9.5%), decreased libido (9.5%), tremor (4.7%), and tachycardia (4.7%). SRT plasma levels ranged from 2.82 to 112.20 ng/ml (mean=40.42 ng/ml, S.D.=26.93). No correlation between SRT plasma levels and clinical improvement or side effects were observed. Drug plasma level determination does not seem be strictly necessary from a clinical point of view but further research seems advisable in patients at risk like elderly and during long-term studies.