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IntroductionAntidepressant overprescribing and unnecessary long-term use are common and can increase the risk of adverse effects and withdrawal symptoms on discontinuation. Although gradual tapering strategies have been proposed, empirical evidence from randomised trials is lacking. This study will compare the efficacy of two antidepressant discontinuation strategies—linear and hyperbolic tapering—in adults with remitted depressive disorders.Methods and analysisThis pragmatic, multicentre, open-label, parallel-group superiority randomised controlled trial will recruit adults (≥18 years) with remitted depressive disorders who have been taking an antidepressant for at least 6 months. During an 8-month recruitment period, participants in outpatient psychiatric and primary care settings will be randomised (1:1) to (a) linear tapering (dose reduced by 50% of the minimum effective dose every 2 weeks until cessation) or (b) hyperbolic tapering (dose reduced by 20–25% every 2 weeks until cessation). The primary outcome is the proportion of participants who fail to discontinue the antidepressant by the end of the predefined tapering schedule or who re-initiate antidepressant therapy within 16 weeks of discontinuation. Secondary outcomes include safety, tolerability (including withdrawal symptoms), acceptability, clinical effectiveness, social functioning, quality of life and cost-effectiveness. Recruiters and participants will be aware of their treatment allocation; however, outcome assessors and the biostatistician will remain blinded throughout follow-up. Validated rating scales measuring depression, anxiety, withdrawal symptoms and social functioning will be administered at baseline and at scheduled follow-up visits up to 36 weeks. Based on observational data, we aim to recruit 150 participants (75 per arm).Ethics and disseminationThe study was approved by institutional Ethics Committees and regulatory authorities. Written informed consent will be obtained from all participants and data processed in accordance with General Data Protection Regulation. Study insurance and pharmacovigilance procedures are in place. Findings will be published in open-access journals, presented at scientific meetings and communicated to policy and regulatory stakeholders.Trial registrationNCT07393919.

Clinical trials and real-world data have shown that long-acting injectable antipsychotics (LAIs) might be an effective therapeutic option also for people with bipolar disorder (BD). However, complementing evidence from mirror-image studies investigating LAIs in BD is scattered and has not been systematically evaluated so far. We thus performed a review of observational mirror-image studies testing the effectiveness of LAI treatment on clinical outcomes in people with BD. Embase, MEDLINE, and PsycInfo electronic databases were systematically searched (via Ovid) up to November 2022. We included six mirror-image studies that compared relevant clinical outcomes between the 12-months after (post-treatment period) and the 12-months before (pre-treatment period) the initiation of a LAI treatment in adults with BD. We found that LAI treatment is associated with a significant reduction in days spent in hospital and number of hospitalizations. Moreover, LAI treatment seems to be associated with a significant decrease in the proportion of individuals with at least one hospital admission, even though data on this outcome were reported by just two studies. In addition, studies consistently estimated a significant reduction of hypo-/manic relapses after LAI treatment initiation, while the effect of LAIs for depressive episodes is less clear. Finally, LAI treatment initiation was associated with a lower number of emergency department visits in the year after LAI initiation. The findings of this review seem to suggest that the use of LAIs is an effective strategy to improve major clinical outcomes in people with BD. Nonetheless, additional research, based on standardized assessments of prevalent polarity and relapses, is needed to identify the clinical characteristics of individuals with BD who are most likely to benefit from a LAI treatment.

Background/Objectives: Both traumatic and stressful events, including major life changes, may contribute to post-traumatic stress symptoms (PTS), often associated with anxiety and depression. Feelings of loneliness may influence these relationships, whilst social support seems to mitigate the effects of stressful events on mental health. Our study thus aimed to evaluate the mediating role of loneliness in the relationships between PTS and both anxiety and depressive symptoms among university students. Methods: The data were from the CAMPUS study (0058642/21; FHMS 20-21 157), a survey on university students’ mental health in Italy and the UK. Using a logit model, mediation analyses were carried out to test whether the relationships between PTS and both anxiety and depressive symptoms might be mediated by loneliness. A path analysis was then performed to jointly test the associations between the Impact of Event Scale—Revised (IES-R)’s subscales and clinical domains. Results: Positive associations were found between PTS and both anxiety (p < 0.001) and depressive symptoms (p < 0.001). However, loneliness mediated approximately 22% of the effect of the PTS on anxiety symptoms (indirect effect: 1.04, 95% CI: 0.59; 1.48, p < 0.001) and approximately 33% of the effect of the PTS on depressive symptoms (indirect effect: 1.81, 95% CI: 1.22; 2.39, p < 0.001). Furthermore, the path analysis indicated associations between the IES-R’s hyperarousal subscale and both anxiety (coeff.: 0.34, p < 0.001) and depressive symptoms (coeff.: 0.27, p < 0.001). Conclusions: Along with the associations between PTS and both anxiety and depressive symptoms, our findings highlight the key role of loneliness in both these associations. Targeted interventions to reduce loneliness, especially for students exposed to traumatic events, may ultimately improve their mental health.

Background: Valproic acid (VPA)-induced hyperammonemia is a common condition whose clinical presentations can range from asymptomatic cases to severe hyperammonemic encephalopathy. This can happen at any stage of treatment and is difficult to predict, as it often occurs without any alteration in liver function tests. Objectives: We aimed at exploring the association between hyperammonemia and clinical/biochemical characteristics among inpatients with mental disorders. Design: This cross-sectional study was conducted on adults consecutively admitted to two acute psychiatric inpatient units in the Milan metropolitan area from October 2022 to October 2024. All participants were treated with oral VPA during hospitalization. Methods: Sociodemographic, clinical, and biochemical data were retrieved from clinical interviews and electronic chart reviews. Univariate analyses and multiple logistic regressions were used to assess the association between hyperammonemia and candidate variables. Results: We included 130 participants (mean age: 38.2 ± 15.3 years; males: 77.7%). Bipolar I (36.9%), personality (31.5%), and schizophrenia spectrum (20.8%) disorders were the most common diagnoses. Mean serum ammonium levels were 46.4 ± 17.5 μmol/L, with hyperammonemia observed in 52 (40.0%) participants. Univariate analyses estimated an association of hyperammonemia with male sex, the concomitant use of 2+ medications (besides VPA), treatment with antipsychotics, and a diagnosis of alcohol use disorder (AUD). No further clinical/biochemical features were associated with hyperammonemia, including serum VPA levels and daily dose of VPA. Regression models showed that the concomitant use of 2+ other medications (coeff. = 1.03, p = 0.018) and AUD (coeff. = 1.32, p = 0.018), but not male sex (p = 0.12) and the use of antipsychotics (p = 0.09), were associated with hyperammonemia. Conclusion: Our findings highlight the potential influence of AUD and polypharmacy on the risk of hyperammonemia in subjects treated with oral VPA. Additional studies are needed to confirm these associations and to test their potential causal role in hyperammonemia. Clinical implications for limiting polypharmacy in people treated with oral VPA should be considered. Plain language summary High ammonium levels in psychiatric patients on valproic acid: associations with clinical conditions and biochemical factors Background: This study explored the correlation between high ammonium levels (hyperammonemia) and clinical and biochemical factors in psychiatric patients taking valproic acid (VPA). Hyperammonemia is a common side effect of VPA, ranging from no symptoms to severe confusion, and can occur without changes in liver function tests. Methods: The study included 130 adults admitted to two psychiatric units in Milan from October 2022 to October 2024. All patients were receiving VPA during their hospitalization. The team collected medical histories, test results, and other health information, then analyzed potential correlations using statistical models. Results: The patients, mostly male (77.7%) with an average age of 38, were diagnosed mainly with bipolar I disorder (36.9%), personality disorders (31.5%), or schizophrenia-related conditions (20.8%). 52 (40.0%) had high ammonium levels. The analysis found that hyperammonemia was more common in patients taking two or more other medications along with VPA, those using antipsychotics, and individuals with alcohol use disorder (AUD). However, after adjusting for multiple factors, only AUD and taking multiple medications remained significantly linked to high ammonium levels. Interestingly, neither the daily dose of VPA nor blood VPA levels predicted hyperammonemia. This means that high ammonium levels can occur regardless of the amount of VPA in the body. Conclusions: The results highlight the risks of using many medications together and the impact of alcohol use in patients on VPA. Reducing the number of medications may help lower the chance of hyperammonemia. Additional studies are needed to confirm these associations and to test their potential causal role on hyperammonemia. These insights could guide doctors in improving the safety of VPA treatment, especially for patients with alcohol use issues or those on multiple medications.

Background The predominant polarity in bipolar disorder (BD) is defined by the skewness of mood episodes towards either the manic or depressive pole. However, since the predominant polarity can only be established over the long term, it is crucial to identify predictors of illness trajectory. Among these factors, the polarity at onset has been suggested to hold important implications, even though research in this field is not entirely consistent so far. In this retrospective study, we thus explored whether the polarity of the first episode can predict the predominant polarity in BD. Methods We included subjects with BD consecutively referred to two acute inpatient units in the Milan metropolitan area from May 2020 to January 2024. Following Barcelona criteria, a manic (mPP) and a depressive (dPP) predominant polarity were defined as having a ratio ≥ 2:1 of past manic/hypomanic or depressive episodes, respectively. The relationship between first episode polarity and either mPP or dPP was examined using multivariable logistic regression models. A path analysis was then performed to jointly test the associations between putative variables and the predominant polarity. Results This study included 128 participants. Regression models estimated an association between a manic onset and a mPP (β = 3.23, p < 0.001) as well as between a depressive onset and a dPP (β = 3.65, p < 0.001). Participants with a mPP showed a lower age at onset (β = − 0.13, p = 0.004), while subjects diagnosed with BD type I were less likely to show a dPP (β = − 2.09, p = 0.024). The path analysis highlighted an association between earlier onset and the likelihood of a first episode of manic polarity (coeff. = − 1.39, p = 0.021). A manic onset was associated with a higher likelihood of mPP (coeff. = 3.46, p < 0.001) and a lower likelihood of dPP (coeff. = − 3.71, p < 0.001). Consistently, participants with a manic onset were more likely to experience a lower number of depressive episodes (coeff. = − 1.36, p < 0.001). Finally, cannabis use disorder was associated with a lower number of depressive episodes (coeff. = − 0.57, p = 0.011). Conclusions These results provide important insights into the likely predictive value of first episode polarity in relation to the predominant polarity in BD. Though future studies validating these findings are needed, the polarity at onset may serve as an early marker for illness trajectory.

Risperidone was the first second-generation antipsychotic to be developed as a long-acting injectable (LAI). In the early 2000s, a risperidone microsphere formulation, intramuscularly administered every 2 weeks (BW-RLAI), was introduced. To date, five different risperidone LAI formulations have been marketed - including a second biweekly microsphere injection (LY03004), a newer monthly intramuscular formulation using in situ microparticles (ISM) technology that does not require an oral risperidone run-in, and two subcutaneous formulations (RBP-7000 and TV-46000). Understanding the advantages and limitations of each option is essential for tailoring treatment regimens based on clinical needs and patient preferences. In this review, with the aim of offering insights for clinical practice and future research, we provide a comprehensive synthesis of the currently available risperidone LAI formulations, examining their efficacy and safety for the treatment of schizophrenia and bipolar I disorder. While evidence supporting the efficacy, tolerability, and safety of risperidone LAI for schizophrenia is available for all marketed formulations to date, advantages for newer formulations, such as longer dosing intervals without oral supplementation, are also reviewed. In addition, although the Food and Drug Administration approved the biweekly LAIs for bipolar I disorder, there is no data on effectiveness of the other risperidone LAI formulations for this indication so far. The variety of the available risperidone LAI options is likely to enable a more personalized treatment approach. To facilitate this, healthcare providers should develop a comprehensive understanding of these formulations to select the most suitable option. While risperidone ISM, RBP-7000, and TV-46000 may enhance treatment feasibility and adherence, further research is needed to build an evidence base comparable to that available for BW-RLAI, particularly in the treatment of BD.

Background and objectives: Readmissions of youths hospitalized for a severe mental disorder are common events and bear a remarkable human, social, and economic burden. The current study aimed at evaluating predictors of 1-year rehospitalization in a sample of adolescents and young adults with severe mental disorders. Materials and Methods: Data for ≤25-year-old inpatients with a severe mental disorder and consecutively admitted between 1 January 2016 and 30 June 2019 were collected. Subjects were retrospectively assessed over a follow-up period of one year after the index discharge to track readmissions—i.e., the primary outcome variable. Standard descriptive statistics were used. The association between variables and 1-year rehospitalization was estimated using the univariate Cox proportional hazards regression model. We then carried out a multivariable Cox regression model, also estimating the covariate-adjusted survivor function. Hazard ratios (HRs) with related 95% confidence intervals (95% CIs) were provided. Results: The final sample included 125 individuals. The multivariable Cox regression model estimated that co-occurring substance use disorders (HR = 2.14; 95% CI: 1.08 to 4.26; p = 0.029) and being admitted for a suicide attempt (HR = 2.49; 95% CI: 1.13 to 5.49; p = 0.024) were both significant predictors of 1-year rehospitalization. Conclusions: Our study showed that comorbid substance use disorders and being admitted for a suicide attempt were predictors of early readmission in youths with severe mental disorders. Although their generalizability is limited, our findings could contribute to improve the quality of young patients’ mental health care by identifying vulnerable subjects who may benefit from tailored interventions to prevent rehospitalizations.

The responsiveness of professionals working with children and families is of key importance for child maltreatment early identification. However, this might be undermined when multifaceted circumstances, such as the COVID-19 pandemic, reduce interdisciplinary educational activities. Thanks to technological developments, digital platforms seem promising in dealing with new challenges for professionals’ training. We examined a digital approach to child maltreatment training through the ERICA project experience (Stopping Child Maltreatment through Pan-European Multiprofessional Training Programme). ERICA has been piloted during the pandemic in seven European centers involving interconnected sectors of professionals working with children and families. The training consisted of interactive modules embedded in a digital learning framework. Different aspects (technology, interaction, and organization) were evaluated and trainers’ feedback on digital features was sought. Technical issues were the main barrier, however, these did not significantly disrupt the training. The trainers perceived reduced interaction between participants, although distinct factors were uncovered as potential favorable mediators. Based on participants’ subjective experiences and perspectives, digital learning frameworks for professionals working with children and families (such as the ERICA model nested in its indispensable adaptation to an e-learning mode) can represent a novel interactive approach to empower trainers and trainees to tackle child maltreatment during critical times such as a pandemic, and as an alternative to more traditional learning frameworks.

Schizophrenia is a severe mental illness causing a high degree of disability. First- and second-generation antipsychotics (FGAs and SGAs) represent key resources for its acute and long-term management. Since a poor adherence to oral treatments may negatively impact the course of the disorder, long-acting injectable antipsychotics (LAIs) are often used to reduce clinical relapses. Notwithstanding their potential beneficial features, LAIs use in clinical practice remains somewhat hampered by the limited amount of relevant systematic information. This review thus aims at providing a clinical, practical guidance for the use of LAIs in the treatment of schizophrenia. We synthetized main information on indications, dosage, and administration of LAIs approved by the US Food and Drug Administration (FDA) and/or in EU countries, as well as evidence from the most recent systematic reviews and meta-analyses. Currently available information, though heterogeneous, shows that LAIs can prevent relapses and rehospitalizations, improving clinical outcomes and favouring sustained remission among people with schizophrenia. The use of SGA LAIs is supported by more robust evidence than FGA LAIs. Along with their positive impact on the prevention of treatment discontinuation, some LAIs might also enhance individual global functioning and quality of life, without additional adverse events or health-care costs, as compared with oral antipsychotics. Although which LAIs can be considered a first-choice option, as well as their superiority over oral antipsychotics, remain unclear issues, this review offers a comprehensive overview of information available on the use of LAIs for people with schizophrenia, providing clinicians with practical guidance in terms of efficacy and acceptability of single agents. Literature gaps and future research needs are also described.