Durability of Effects of Cognitive Remediation on Cognition and Psychosocial Functioning in Schizophrenia: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

OBJECTIVE: Cognitive remediation provides substantial improvements in cognitive performance and real-world functioning for people living with schizophrenia, but the durability of these benefits needs to be reassessed and better defined. The aims of this study were to provide a comprehensive assessment of the durability of the benefits of cognitive remediation for cognition and functioning in people living with schizophrenia and evaluating potential moderators of effects. METHODS: A systematic search was conducted in PubMed, Scopus, and PsycINFO, and reference lists of included articles and Google Scholar were inspected. Eligible studies were randomized clinical trials of cognitive remediation in patients diagnosed with schizophrenia spectrum disorders in which follow-up assessments were included. Screening and data extraction were performed by at least two independent reviewers. Cohen's d was used to measure outcomes. Primary outcomes were changes in cognition and functioning from baseline to conclusion of follow-up. Moderators of the durability of effects were assessed. RESULTS: Of 2,840 identified reports, 281 full texts were assessed and 130 reports on 67 studies with 5,334 participants were included. Cognitive remediation produced statistically significant positive effects that persisted at the end of follow-up in global cognition (d=0.23) and in global functioning (d=0.26). Smaller study samples and single-center studies were associated with better cognitive outcomes; longer treatment and follow-up duration, techniques for transferring cognitive gains to the real world, integration with psychiatric rehabilitation, group format of delivery, and more female participants in the sample were associated with better functional outcomes. CONCLUSIONS: Cognitive remediation provides durable improvements in cognition and functioning in schizophrenia. This finding corroborates the notion that cognitive remediation should be implemented more widely in clinical and rehabilitation practice.

Application of cognitive remediation in the world: new experiences from two schizophrenia rehabilitation centers in Togo and Benin.

PURPOSE: People with schizophrenia in Sub-Saharan Africa often live in very difficult conditions, suffer important social isolation and usually do not receive any kind of treatment. In this context, some non-governmental initiatives have come to light, providing accommodation, food, primary healthcare, medications and, in some cases, education and rehabilitation. The aims of this study were to assess feasibility, effects, and acceptability of a Cognitive Remediation Therapy (CRT) intervention in the particular context of psychiatric rehabilitation in Togo and Benin. METHODS: Patients diagnosed with schizophrenia accessing the "Saint Camille" association rehabilitation centers in Togo and Benin during the enrollment period were allocated consecutively with a 1:1 proportion to receive a manualized CRT intervention (46 one-hour sessions over 14 weeks) or continuing Treatment As Usual (TAU). The assessment included validated measures of cognitive performance and real-world functioning and was performed at baseline and at the conclusion of treatment. RESULTS: All subjects that were invited into the study agreed to participate and completed the intervention, for a total of 36 participants. CRT produced greater improvements than TAU in processing speed, working memory, verbal memory, cognitive flexibility, and executive functions measures, with moderate to large effect sizes, in particular in processing speed and working memory domains. CONCLUSIONS: CRT represents a feasible and effective psychosocial intervention that can be implemented even in contexts with very limited resources, and could represent an important instrument to promote the rehabilitation process of people living with schizophrenia in low-income countries.

Efficacy of Functional Remediation on Cognitive and Psychosocial Functioning in Patients with Bipolar Disorder: Study Protocol for a Randomized Controlled Study.

BACKGROUND: Neurocognitive impairment is a prominent characteristic of bipolar disorder (BD), linked with poor psychosocial functioning. This study's purpose is to evaluate the effectiveness of functional remediation (FR) in enhancing neurocognitive dysfunctions in a sample of remitted patients with diagnosis of BD in comparison to treatment as usual-TAU. To quantify the neurocognitive damage, the Brief Assessment of Cognition in Affective Disorders (BAC-A) will be used, and the overall psychosocial functioning will be measured with the Functioning Assessment Short Test-FAST. METHODS: The randomized, rater-blinded, controlled study will include two arms (1:1) encompassing 54 outpatients with diagnosis of BD-I and BD-II, as defined by the DSM-5 criteria. In the experimental phase, remitted patients aged 18-55 years will be involved. At the baseline, at the end of intervention and at the 6-month follow-up, patients will be evaluated using clinical scales (Young Mania Rating Scale (Y-MRS) and Hamilton Depression Rating Scale (HAM-D)). Neurocognitive measurements and psychosocial functioning will be valued, respectively, with BAC-A and FAST. DISCUSSION: The primary expected outcome is that following FR intervention, patients will exhibit improved cognitive abilities and psychosocial outcomes compared to the participants in the TAU group. It is now recognized that neurocognitive deficits are potential predictors of functional outcome in patients with BD. In recent years, there has been a growing interest in the implementation of interventions that, in addition to symptomatic remission, are also aimed at neurocognitive dysfunctions in order to achieve a recovery of psychosocial functioning.

Acceptability of cognitive remediation for schizophrenia: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Acceptability is an important factor for predicting intervention use and potential treatment outcomes in psychosocial interventions. Cognitive remediation (CR) improves cognition and functioning in people with a diagnosis of schizophrenia, but its acceptability, and the impact of participants and treatment characteristics, remain to be investigated. Few studies provide a direct measure of acceptability, but treatment drop-out rates are often available and represent a valid surrogate. METHOD: The systematic search conducted for the most comprehensive CR outcomes database for schizophrenia was updated in December 2020. Eligible studies were randomized clinical trials comparing CR with any other control condition in patients diagnosed with schizophrenia spectrum disorders and that also reported drop-out in treatment and control arms separately. Acceptability was measured as odd-ratios (OR) of drop-out. RESULTS: Of 2119 identified reports, 151 studies, reporting 169 comparisons between CR and control interventions with 10 477 participants were included in the analyses. The overall rate of drop-out was 16.58% for CR programs and 15.21% for control conditions. In the meta-analysis, no difference emerged between CR interventions and controls [OR 1.10, 95% confidence interval (CI) 0.96-1.25, p = 0.177]. Factors improving acceptability were: inpatient only recruitment, participants with fewer years of education and lower premorbid IQ, the presence of all CR core elements, and the presence of techniques to transfer cognitive gains into real-world functioning. CONCLUSIONS: CR for people diagnosed with schizophrenia is effective and has a good acceptability profile, similar to that of other evidence-based psychosocial interventions.

The Impact of the COVID-19 Pandemic and Associated Control Measures on the Mental Health of the General Population : A Systematic Review and Dose-Response Meta-analysis.

BACKGROUND: To what extent the COVID-19 pandemic and its containment measures influenced mental health in the general population is still unclear. PURPOSE: To assess the trajectory of mental health symptoms during the first year of the pandemic and examine dose-response relations with characteristics of the pandemic and its containment. DATA SOURCES: Relevant articles were identified from the living evidence database of the COVID-19 Open Access Project, which indexes COVID-19-related publications from MEDLINE via PubMed, Embase via Ovid, and PsycInfo. Preprint publications were not considered. STUDY SELECTION: Longitudinal studies that reported data on the general population's mental health using validated scales and that were published before 31 March 2021 were eligible. DATA EXTRACTION: An international crowd of 109 trained reviewers screened references and extracted study characteristics, participant characteristics, and symptom scores at each timepoint. Data were also included for the following country-specific variables: days since the first case of SARS-CoV-2 infection, the stringency of governmental containment measures, and the cumulative numbers of cases and deaths. DATA SYNTHESIS: In a total of 43 studies (331 628 participants), changes in symptoms of psychological distress, sleep disturbances, and mental well-being varied substantially across studies. On average, depression and anxiety symptoms worsened in the first 2 months of the pandemic (standardized mean difference at 60 days, -0.39 [95% credible interval, -0.76 to -0.03]); thereafter, the trajectories were heterogeneous. There was a linear association of worsening depression and anxiety with increasing numbers of reported cases of SARS-CoV-2 infection and increasing stringency in governmental measures. Gender, age, country, deprivation, inequalities, risk of bias, and study design did not modify these associations. LIMITATIONS: The certainty of the evidence was low because of the high risk of bias in included studies and the large amount of heterogeneity. Stringency measures and surges in cases were strongly correlated and changed over time. The observed associations should not be interpreted as causal relationships. CONCLUSION: Although an initial increase in average symptoms of depression and anxiety and an association between higher numbers of reported cases and more stringent measures were found, changes in mental health symptoms varied substantially across studies after the first 2 months of the pandemic. This suggests that different populations responded differently to the psychological stress generated by the pandemic and its containment measures. PRIMARY FUNDING SOURCE: Swiss National Science Foundation. (PROSPERO: CRD42020180049).

Maintenance Treatment With Antipsychotic Drugs in Schizophrenia: A Cochrane Systematic Review and Meta-analysis.

Antipsychotic drugs are the mainstay of treatment of schizophrenia, and are known to reduce acute symptoms of the disorder. An original version of the current review, published in 2012, examined whether antipsychotics are effective for relapse prevention, compared to withdrawing these agents for people with schizophrenia or schizophrenia-like psychoses, based on evidence from randomized trials. The current report of the update of the review is focused on some newly investigated outcomes: rates of remission and recovery, change in social functioning and in quality of life. The updated review included 75 randomized controlled trials (RCTs) published from 1959 to 2017, involving 9145 participants. Although some potential sources of bias limited the overall quality, the efficacy of antipsychotic drugs for maintenance treatment in schizophrenia was clear and robust to a series of sensitivity analyses. Antipsychotic drugs were more effective than placebo in preventing relapse at 1 year (drug 24% versus placebo 61%, 30 RCTs, n = 4249, RR = 0.38, 95% CI = 0.32 to 0.45) and in reducing hospitalization (drug 7% versus placebo 18%, 21 RCTs, n = 3558, RR = 0.43, 95% CI = 0.32 to 0.57). Quality of life appeared to be better in drug-treated participants (7 RCTs, n = 1573, SMD = -0.32, 95% CI = -0.57 to -0.07); the same for social functioning (15 RCTs, n = 3588, SMD = -0.43, 95% CI = -0.53 to -0.34). Although based on data from fewer studies, maintenance treatment apparently increased the possibility to achieve remission of symptoms (drug 53%, placebo 31%; 7 RCTs, 867 participants; RR = 1.73, 95% CI = 1.20 to 2.48) and to sustain it over 6 months (drug 36%, placebo 26%; 8 RCTs, 1807 participants; RR = 1.67, 95% CI = 1.28 to 2.19). There were no data on recovery. Antipsychotic drugs as a group were associated with more participants experiencing side effects such as movement disorders (e.g., at least one movement disorder: drug 14% versus placebo 8%, 29 RCTs, n = 5276, RR 1.52, 95% CI = 1.25 to 1.85) and weight gain (drug 9% versus placebo 6%, 19 RCTs, n = 4767, RR = 1.69, 95% CI = 1.21 to 2.35, NNTH = 25, 95% CI = 20 to 50). For people with schizophrenia, the evidence suggests that maintenance on antipsychotic drugs does not only prevent relapses and rehospitalizations, but that patients also benefit in terms of quality of life, functioning and sustained remission. These positive effects must be weighed against the backdrop of the adverse effects of antipsychotics.

Pharmacological and dietary-supplement treatments for autism spectrum disorder: a systematic review and network meta-analysis.

BACKGROUND: There is still no approved medication for the core symptoms of autism spectrum disorder (ASD). This network meta-analysis investigated pharmacological and dietary-supplement treatments for ASD. METHODS: We searched for randomized-controlled-trials (RCTs) with a minimum duration of seven days in ClinicalTrials.gov, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (from inception up to July 8, 2018), CENTRAL and PubMed (up to November 3, 2021). The co-primary outcomes were core symptoms (social-communication difficulties-SCD, repetitive behaviors-RB, overall core symptoms-OCS) measured by validated scales and standardized-mean-differences (SMDs). Associated symptoms, e.g., irritability/aggression and attention-deficit/hyperactivity disorder (ADHD) symptoms, dropouts and important side-effects, were investigated as secondary outcomes. Studies in children/adolescents and adults were analyzed separately in random-effects pairwise and network meta-analyses. RESULTS: We analyzed data for 41 drugs and 17 dietary-supplements, from 125 RCTs (n = 7450 participants) in children/adolescents and 18 RCTs (n = 1104) in adults. The following medications could improve at least one core symptom domain in comparison with placebo: aripiprazole (k = 6 studies in analysis, SCD: SMD = 0.27 95% CI [0.09, 0.44], RB: 0.48 [0.26, 0.70]), atomoxetine (k = 3, RB:0.49 [0.18, 0.80]), bumetanide (k = 4, RB: 0.35 [0.09, 0.62], OCS: 0.61 [0.31, 0.91]), and risperidone (k = 4, SCM: 0.31 [0.06, 0.55], RB: 0.60 [0.29, 0.90]; k = 3, OCS: 1.18 [0.75, 1.61]) in children/adolescents; fluoxetine (k = 1, RB: 1.20 [0.45, 1.96]), fluvoxamine (k = 1, RB: 1.04 [0.27, 1.81]), oxytocin (k = 6, RB:0.41 [0.16, 0.66]) and risperidone (k = 1, RB: 0.97 [0.21,1.74]) in adults. There were some indications of improvement by carnosine, haloperidol, folinic acid, guanfacine, omega-3-fatty-acids, probiotics, sulforaphane, tideglusib and valproate, yet imprecise and not robust. Confidence in these estimates was very low or low, except moderate for oxytocin. Medications differed substantially in improving associated symptoms, and in their side-effect profiles. LIMITATIONS: Most of the studies were inadequately powered (sample sizes of 20-80 participants), with short duration (8-13 weeks), and about a third focused on associated symptoms. Networks were mainly star-shaped, and there were indications of reporting bias. There was no optimal rating scale measuring change in core symptoms. CONCLUSIONS: Some medications could improve core symptoms, although this could be likely secondary to the improvement of associated symptoms. Evidence on their efficacy and safety is preliminary; therefore, routine prescription of medications for the core symptoms cannot be recommended. Trial registration PROSPERO-ID CRD42019125317.

Efficacy and tolerability of Brain Stimulation interventions in Borderline Personality Disorder: state of the art and future perspectives - A systematic review.

Treating Borderline Personality Disorder (BPD) is a major challenge for psychiatrists. As Brain Stimulation represents an alternative approach to treat psychiatric disorders, our systematic review is the first to focus on both invasive and Non-Invasive Brain Stimulation (NIBS) interventions in people living with BPD, examining clinical effects over core features and comorbid conditions. Following PRISMA guidelines, out of 422 original records, 24 papers were included regarding Deep Brain Stimulation (n = 1), Electroconvulsive therapy (n = 5), Transcranial Magnetic Stimulation (n = 13) and transcranial Direct Current Stimulation (n = 5). According to impulsivity and emotional dysregulated domain improvements, NIBS in BPD appears to restore frontolimbic network deficiencies. NIBS seems also to modulate depressive features. Safety and tolerability profiles for each technique are discussed. Despite encouraging results, definitive recommendations on Brain Stimulation in BPD are mitigated by protocols heterogeneity, lack of randomized controlled trials and poor quality of included studies, including high risk of methodological biases. To serve as guide for future systematic investigations, protocols optimization proposals are provided, focusing on alternative stimulation sites and suggesting a NIBS symptom-based approach.

Comparative efficacy and tolerability of 32 oral and long-acting injectable antipsychotics for the maintenance treatment of adults with schizophrenia: a systematic review and network meta-analysis.

BACKGROUND: Schizophrenia is a common, severe, and usually chronic disorder. Maintenance treatment with antipsychotic drugs can prevent relapse but also causes side-effects. We aimed to compare the efficacy and tolerability of antipsychotics as maintenance treatment for non-treatment resistant patients with schizophrenia. METHODS: In this systematic review and network meta-analysis, we searched, without language restrictions, the Cochrane Schizophrenia Group's specialised register between database inception and April 27, 2020, PubMed from April 1, 2020, to Jan 15, 2021, and the lists of included studies from related systematic reviews. We included randomised controlled trials (RCTs; ≥12 weeks of follow-up) that recruited adult participants with schizophrenia or schizoaffective disorder with stable symptoms who were treated with antipsychotics (monotherapy; oral or long-acting injectable) or placebo. We excluded RCTs of participants with specific comorbidities or treatment resistance. In duplicate, two authors independently selected eligible RCTs and extracted aggregate data. The primary outcome was the number of participants who relapsed and was analysed by random-effects, Bayesian network meta-analyses. The study was registered on PROSPERO, CRD42016049022. FINDINGS: We identified 4157 references through our search, from which 501 references on 127 RCTs of 32 antipsychotics (comprising 18 152 participants) were included. 100 studies including 16 812 participants and 30 antipsychotics contributed to our network meta-analysis of the primary outcome. All antipsychotics had risk ratios (RRs) less than 1·00 when compared with placebo for relapse prevention and almost all had 95% credible intervals (CrIs) excluding no effect. RRs ranged from 0·20 (95% CrI 0·05-0·41) for paliperidone oral to 0·65 (0·16-1·14) for cariprazine oral (moderate-to-low confidence in estimates). Generally, we interpret that there was no clear evidence for the superiority of specific antipsychotics in terms of relapse prevention because most comparisons between antipsychotics included a probability of no difference. INTERPRETATION: As we found no clear differences between antipsychotics for relapse prevention, we conclude that the choice of antipsychotic for maintenance treatment should be guided mainly by their tolerability. FUNDING: The German Ministry of Education and Research and Oxford Health Biomedical Research Centre.

Effectiveness, Core Elements, and Moderators of Response of Cognitive Remediation for Schizophrenia: A Systematic Review and Meta-analysis of Randomized Clinical Trials.

Importance: Cognitive impairment is a core feature of schizophrenia, with negative consequences on functional outcomes. Although cognitive remediation (CR) is effective and mentioned in treatment guidance for schizophrenia, its active ingredients and ideal candidates are still debated. Objective: To provide a comprehensive update on CR effectiveness for cognition and functioning in schizophrenia and analyze the core ingredients of efficacy and role of patient characteristics. Data Sources: The reference list of the last comprehensive meta-analysis in 2011 was screened against eligibility criteria. Then, electronic databases (PubMed, Scopus, and PsycInfo) were systematically searched for articles published from January 2011 to February 2020. Reference lists of included articles and relevant reviews were hand searched, and Google Scholar was manually inspected. Study Selection: Eligible studies were randomized clinical trials comparing CR with any other control condition in patients diagnosed with schizophrenia spectrum disorders (with an unrestricted clinical status). Screening was performed by at least 2 independent reviewers. Data Extraction and Synthesis: The PRISMA guidelines were followed. Study data were independently extracted and pooled using random-effect models. Cohen d was used to measure outcomes. Trial methodological quality was evaluated with the Clinical Trials Assessment Measure. Main Outcomes and Measures: Primary outcomes were changes in global cognition and overall functioning from baseline to after treatment, subsequently investigated through metaregressions, subgroup, and sensitivity analyses based on prespecified hypotheses, to identify potential moderators of response associated with treatment modality and patient characteristics. Results: Of 1815 identified reports, 358 full texts were assessed and 194 reports on 130 studies were included. Based on 130 studies with 8851 participants, CR was effective on cognition (d, 0.29 [95% CI, 0.24-0.34]) and functioning (d, 0.22 [95% CI, 0.16-0.29]). An active and trained therapist (cognition: χ21, 4.14; P = .04; functioning: χ21, 4.26; P = .04), structured development of cognitive strategies (cognition: χ21, 9.34; P = .002; functioning: χ21, 8.12; P = .004), and integration with psychosocial rehabilitation (cognition: χ21, 5.66; functioning: χ21, 12.08) were crucial ingredients of efficacy. Patients with fewer years of education (global cognition: coefficient, -0.055 [95% CI, -0.103 to -0.006]; P = .03; global functioning: coefficient, -0.061 [95% CI, -0.112 to -0.011]; P = .02), lower premorbid IQ (global functioning: coefficient, -0.013 [-0.025 to -0.001]; P = .04), and higher baseline symptom severity (global cognition: coefficient, 0.006 [95% CI, 0.002 to 0.010]; P = .005) emerged as optimal candidates. Conclusions and Relevance: These findings show that CR is an evidence-based intervention that should be included consistently into clinical guidelines for the treatment of individuals with schizophrenia and implemented more widely in clinical practice.

Social Cognition in a Research Domain Criteria Perspective: A Bridge Between Schizophrenia and Autism Spectra Disorders.

Schizophrenia and autism spectra disorders are currently conceptualized as distinct clinical categories. However, the relationship between these two nosological entities has been revisited in recent years due to the evidence that they share some important clinical and neurobiological features, putting into question the nature and the extent of their commonalities and differences. In this respect, some core symptoms that are present in both disorders, such as social cognitive deficits, could be a primary target of investigation. This review briefly summarizes the commonalities and overlapping features between schizophrenia and autism spectra disorders in social cognitive functions, considering this construct in a Research Domain Criteria perspective. The clinical manifestation of deficits in social cognition are similar in schizophrenia spectrum disorders and autism spectrum disorders, and brain areas that appear to be altered in relation to these impairments are largely shared; however, the results of various studies suggest that, in some cases, the qualitative nature of these alterations may be different in the two spectra. Moreover, relevant differences could be present at the level of brain networks and connections. More research is required in this field, regarding molecular and genetic aspects of both spectra, to better define the neurobiological mechanisms involved in social cognition deficits, with the objective of developing specific and targeted treatments.

Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis.

BACKGROUND: Placebo response in autism spectrum disorder (ASD) might dilute drug-placebo differences and hinder drug development. Therefore, this meta-analysis investigated placebo response in core symptoms. METHODS: We searched ClinicalTrials.gov , CENTRAL, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (up to July 8, 2018), and PubMed (up to July 4, 2019) for randomized pharmacological and dietary supplement placebo-controlled trials (RCTs) with a minimum of seven days of treatment. Single-group meta-analyses were conducted using a random-effects model. Standardized mean changes (SMC) of core symptoms in placebo arms were the primary outcomes and placebo positive response rates were a secondary outcome. Predictors of placebo response were investigated with meta-regression analyses. The protocol was registered with PROSPERO ID CRD42019125317 . RESULTS: Eighty-six RCTs with 2360 participants on placebo were included in our analysis (87% in children/adolescents). The majority of trials were small, single-center with a duration of 8-12 weeks and published after 2009. Placebo response in social-communication difficulties was SMC = - 0.32, 95% CI [- 0.39, - 0.25], in repetitive behaviors - 0.23[- 0.32, - 0.15] and in scales measuring overall core symptoms - 0.36 [- 0.46, - 0.26]. Overall, 19%, 95% CI [16-22%] of participants were at least much improved with placebo. Caregiver (vs. clinician) ratings, lower risk of bias, flexible-dosing, larger sample sizes and number of sites, less recent publication year, baseline levels of irritability, and the use of a threshold of core symptoms at inclusion were associated with larger placebo response in at least a core symptom domain. LIMITATIONS: About 40% of the trials had an apparent focus on core symptoms. Investigation of the differential impact of predictors on placebo and drug response was impeded by the use of diverse experimental interventions with essentially different mechanisms of action. An individual-participant-data meta-analysis could allow for a more fine-grained analysis and provide more informative answers. CONCLUSIONS: Placebo response in ASD was substantial and predicted by design- and participant-related factors, which could inform the design of future trials in order to improve the detection of efficacy in core symptoms. Potential solutions could be the minimization and careful selection of study sites as well as rigorous participant enrollment and the use of measurements of change not solely dependent on caregivers.

Maintenance treatment with antipsychotic drugs for schizophrenia.

BACKGROUND: The symptoms and signs of schizophrenia have been linked to high levels of dopamine in specific areas of the brain (limbic system). Antipsychotic drugs block the transmission of dopamine in the brain and reduce the acute symptoms of the disorder. An original version of the current review, published in 2012, examined whether antipsychotic drugs are also effective for relapse prevention. This is the updated version of the aforesaid review. OBJECTIVES: To review the effects of maintaining antipsychotic drugs for people with schizophrenia compared to withdrawing these agents. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials including the registries of clinical trials (12 November 2008, 10 October 2017, 3 July 2018, 11 September 2019). SELECTION CRITERIA: We included all randomised trials comparing maintenance treatment with antipsychotic drugs and placebo for people with schizophrenia or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data we calculated risk ratios (RR) and their 95% confidence intervals (CIs) on an intention-to-treat basis based on a random-effects model. For continuous data, we calculated mean differences (MD) or standardised mean differences (SMD), again based on a random-effects model. MAIN RESULTS: The review currently includes 75 randomised controlled trials (RCTs) involving 9145 participants comparing antipsychotic medication with placebo. The trials were published from 1959 to 2017 and their size ranged between 14 and 420 participants. In many studies the methods of randomisation, allocation and blinding were poorly reported. However, restricting the analysis to studies at low risk of bias gave similar results. Although this and other potential sources of bias limited the overall quality, the efficacy of antipsychotic drugs for maintenance treatment in schizophrenia was clear. Antipsychotic drugs were more effective than placebo in preventing relapse at seven to 12 months (primary outcome; drug 24% versus placebo 61%, 30 RCTs, n = 4249, RR 0.38, 95% CI 0.32 to 0.45, number needed to treat for an additional beneficial outcome (NNTB) 3, 95% CI 2 to 3; high-certainty evidence). Hospitalisation was also reduced, however, the baseline risk was lower (drug 7% versus placebo 18%, 21 RCTs, n = 3558, RR 0.43, 95% CI 0.32 to 0.57, NNTB 8, 95% CI 6 to 14; high-certainty evidence). More participants in the placebo group than in the antipsychotic drug group left the studies early due to any reason (at seven to 12 months: drug 36% versus placebo 62%, 24 RCTs, n = 3951, RR 0.56, 95% CI 0.48 to 0.65, NNTB 4, 95% CI 3 to 5; high-certainty evidence) and due to inefficacy of treatment (at seven to 12 months: drug 18% versus placebo 46%, 24 RCTs, n = 3951, RR 0.37, 95% CI 0.31 to 0.44, NNTB 3, 95% CI 3 to 4). Quality of life might be better in drug-treated participants (7 RCTs, n = 1573 SMD -0.32, 95% CI to -0.57 to -0.07; low-certainty evidence); probably the same for social functioning (15 RCTs, n = 3588, SMD -0.43, 95% CI -0.53 to -0.34; moderate-certainty evidence). Underpowered data revealed no evidence of a difference between groups for the outcome 'Death due to suicide' (drug 0.04% versus placebo 0.1%, 19 RCTs, n = 4634, RR 0.60, 95% CI 0.12 to 2.97,low-certainty evidence) and for the number of participants in employment (at 9 to 15 months, drug 39% versus placebo 34%, 3 RCTs, n = 593, RR 1.08, 95% CI 0.82 to 1.41, low certainty evidence). Antipsychotic drugs (as a group and irrespective of duration) were associated with more participants experiencing movement disorders (e.g. at least one movement disorder: drug 14% versus placebo 8%, 29 RCTs, n = 5276, RR 1.52, 95% CI 1.25 to 1.85, number needed to treat for an additional harmful outcome (NNTH) 20, 95% CI 14 to 50), sedation (drug 8% versus placebo 5%, 18 RCTs, n = 4078, RR 1.52, 95% CI 1.24 to 1.86, NNTH 50, 95% CI not significant), and weight gain (drug 9% versus placebo 6%, 19 RCTs, n = 4767, RR 1.69, 95% CI 1.21 to 2.35, NNTH 25, 95% CI 20 to 50). AUTHORS' CONCLUSIONS: For people with schizophrenia, the evidence suggests that maintenance on antipsychotic drugs prevents relapse to a much greater extent than placebo for approximately up to two years of follow-up. This effect must be weighed against the adverse effects of antipsychotic drugs. Future studies should better clarify the long-term morbidity and mortality associated with these drugs.

Evidence-Based Integrated Intervention in Patients with Schizophrenia: A Pilot Study of Feasibility and Effectiveness in a Real-World Rehabilitation Setting.

Impairment in real-world functioning remains one of the most problematic challenges that people with schizophrenia have to face. Various psychosocial interventions have proven to be effective in promoting recovery and improving functioning in schizophrenia; however, their implementation and their effectiveness in routine rehabilitation practice are still objects of study. The present pilot study aimed to assess the feasibility and effectiveness on clinical and real-world outcomes of an integrated treatment protocol composed of stable pharmacological treatment, computer-assisted cognitive remediation and social skills training provided in a rehabilitation center. Predictors of functional improvement were also assessed. Seventy-two patients diagnosed with schizophrenia participated in the study. A significant (p < 0.001) improvement in positive, negative and total symptoms, as well as in global clinical severity and real-world functioning outcomes was observed, with a large effect size in positive and total symptoms, global clinical severity and real-world functioning, and a moderate effect size on negative symptoms. Improvement in total symptoms (p < 0.001) and in global clinical severity (p = 0.007) emerged as individual predictors of functional improvement. These findings, although preliminary, suggest that an integrated, evidence-based treatment program is feasible and effective in a real-world rehabilitation context, and that similar interventions should be further implemented in everyday clinical practice.

Antipsychotic drugs v. barbiturates or benzodiazepines used as active placebos for schizophrenia: a systematic review and meta-analysis.

BACKGROUND: Comparisons of antipsychotics with placebo can be biased by unblinding due to side effects. Therefore, this meta-analysis compared the efficacy of antipsychotics for acute schizophrenia in trials using barbiturates or benzodiazepines as active placebos. METHODS: Randomized controlled trials (RCTs) in acute schizophrenia with at least 3 weeks duration and comparing any antipsychotic with barbiturates or benzodiazepines were eligible. ClinicalTrials.gov, CENTRAL, EMBASE, MEDLINE, PsycINFO, PubMed, WHO-ICTRP as well as previous reviews were searched up to 9 January 2018. Two separate meta-analyses, one for barbiturates and one for benzodiazepines, were conducted using random-effects models. The primary outcome was response to treatment, and mean values of schizophrenia rating scales and dropouts were analyzed as secondary outcomes. This study is registered with PROSPERO (CRD42018086263). RESULTS: Seven barbiturate-RCTs (number of participants n = 1736), and two benzodiazepine-RCTs (n = 76) were included in the analysis. The studies were published between 1960 and 1968 and involved mainly chronically ill patients. More patients on antipsychotics in comparison to barbiturates achieved a 'good' response (36.2% v. 16.8%; RR 2.15; 95% CI 1.36-3.41; I2 = 48.9) and 'any' response (57.4% v. 27.8%; RR 2.07; 95% CI 1.35-3.18; I2 = 68.2). In a single small trial (n = 60), there was no difference between antipsychotics and benzodiazepines on 'any' response (74.7% v. 65%; RR 1.15; 95% CI 0.82-1.62). CONCLUSIONS: Antipsychotic drugs were more efficacious than barbiturates, based on a large sample size. Response ratios were similar to those observed in placebo-controlled trials. The results on benzodiazepines were inconclusive due to the small number of studies and participants.

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.

Non-amnestic mild cognitive impairment and sleep complaints: a bidirectional relationship?

BACKGROUND: Prior studies documented that several sleep disorders may coexist in patients affected by Mild Cognitive Impairment (MCI) and Alzheimer disease (AD), and have a strong bidirectional relationship with cognitive decline. AIM: To assess the self-reported sleep quality and daytime sleepiness among subjects affected by MCI and AD at early-stage and healthy controls, and to verify if sleep disturbances might be an indicator of specific cognitive deficits. METHODS: 139 patients (102 MCI, 37 AD) underwent comprehensive neuropsychological, functional, and behavioral assessment, which also included Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI). 80 healthy elderly subjects were used as controls. MCI patients have been divided into Good Sleepers and Bad Sleepers, depending on their reported sleep quality (PSQI global score ≤5/>5). RESULTS: MCI patients experienced more subjective daytime sleepiness than AD matches. As for the subjective sleep quality among MCI patients, 54% of Bad Sleepers met diagnostic criteria for non-amnestic MCI; vice-versa, 73% of Good Sleepers were diagnosed with amnestic-MCI (p = 0.005), independently of depression and anxiety. CONCLUSIONS: MCI patients complain of daytime sleepiness and dysfunction more than AD patients; among MCI patients, Bad Sleepers appear mainly characterized by a non-amnestic cognitive profile.

The Italian Version of the Five-Word Test: A Simple Diagnostic Test for Dementia due to Alzheimer's Disease in Routine Clinical Practice.

BACKGROUND: The five-word test (FWT) is a neuropsychological tool (derived from the Grober and Buschke paradigm), measuring hippocampal memory trace consolidation. The study aimed to validate the test for the Italian language and to verify its ability to discriminate patients affected by mild cognitive impairment and dementia due to Alzheimer's disease from healthy matches. METHODS: 217 subjects (127 controls, 47 MCI due to AD, and 43 AD) underwent neuropsychological evaluation. The Spearman rank coefficient (ρ) was used to assess the correlation between immediate (IRS), delayed (DRS), and total score (TRS) of the FWT and correspondent matches of a specific short story test, while receiving operator characteristic (ROC) curves were built to investigate the diagnostic accuracy of both. RESULTS: Correlation between almost all the scores was significant in all the diagnostic subgroups; the ROC curves of the two tests were not statistically different. A TRS of the FWT with a cut-off of ≤9/10 could accurately discriminate AD patients (sensitivity: 97%, specificity: 94%) and MCI due to AD (sensitivity: 76%, specificity: 68%) from control matches. CONCLUSION: FWT is a simple and valid test of hippocampal memory which appears recommendable in routine clinical practice.