Preliminary data from a 4-year mirror-image and multicentre study of patients initiating paliperidone palmitate 6-monthly long-acting injectable antipsychotic: the Paliperidone 2 per Year study.

Background: Paliperidone palmitate 6-monthly (PP6M) is the first long-acting antipsychotic injectable (LAI) to allow for only two medication administrations per year, though there is presently limited insight into its effectiveness and potential added value in real clinical practice conditions. Objectives: To present our ongoing study and draw its preliminary data on patient characteristics initiating PP6M and adherence during the first year of treatment. Methods: The paliperidone 2 per year (P2Y) study is a 4-year, multicentre, prospective mirror-image pragmatic study taking place at over 20 different sites in Europe. The mirror period covers 2 years either side of the PP6M LAI initiation. Retrospective data for the previous 2 years are collected for each patient from the electronic health records. Prospective data are recorded at baseline, 6, 12, 18 and 24 months of drug administration and also cover information on concomitant psychiatric medication, relapses, hospital admissions, side effects, discontinuation and its reasons. Meanwhile, here we present preliminary data from the P2Y study at basal and 6-month period (first and second PP6M administration). Results: At the point of PP6M initiation, the most frequent diagnosis was schizophrenia (69%), the clinical global impression scale mean score was 3.5 (moderately markedly ill) and the rate of previous hospital admissions per patient and year was 0.21. PP6M was initiated after a median of 3-4 years on previous treatment: 146 (73%) from paliperidone palmitate 3-monthly, 37 (19%) from paliperidone palmitate 1-monthly and 17 (9%) from other antipsychotics. The mean dose of the first PP6M was 1098.9 mg. The retention rate at 6 months and 1 year of treatment on PP6M in our cohort was 94%. Conclusion: Patient and clinician preference for LAIs with longer dosing intervals was the main reason for PP6M initiation/switching resulting in high treatment persistence. Future data are needed to evaluate the full impact of PP6M in clinical practice.

1,2-Redox Transpositions of Tertiary Amides.

Reactions capable of transposing the oxidation levels of adjacent carbon atoms enable rapid and fundamental alteration of a molecule's reactivity. Herein, we report the 1,2-transposition of the carbon atom oxidation level in cyclic and acyclic tertiary amides, resulting in the one-pot synthesis of 1,2- and 1,3-oxygenated tertiary amines. This oxidation level transfer was facilitated by the careful orchestration of an iridium-catalyzed reduction with the functionalization of transiently formed enamine intermediates. A novel 1,2-carbonyl transposition is described, and the breadth of this redox transposition strategy has been further explored by the development of aminoalcohol and enaminone syntheses. The diverse ß-functionalized amine products were shown to be multifaceted and valuable synthetic intermediates, accessing challenging biologically relevant motifs.

Relationship between cognition and suicidal behavior in recent-onset psychosis.

Suicidal behavior (SB) is common in first-episode psychosis (FEP), and cognitive impairment has also been described in psychosis. Despite well-established risk factors for SB in psychosis, the role of cognition and insight remains unclear. This study aimed to explore the relationship between history of SB and cognition in recent-onset FEP, distinguishing between neurocognition, social cognition, and metacognition, and including cognitive insight (CI) as a metacognitive variable. The sample consisted of 190 participants with recent-onset FEP recruited from two multicentric studies. Two groups were formed based on presence/absence of a history of SB. Demographic, clinical, and cognitive data were compared by group, including significance level adjustments and size effect calculation. No differences were found regarding demographic, clinical, neurocognitive, social cognition, and metacognitive variables except for CI (18.18 ± 4.87; t = -3.16; p = 0.0020; d = -0.635), which showed a medium effect size. Small to medium effect size were found for attributional style (externalizing bias) (1.15 ± 3.94; t = 2.07; d = 0.482), theory of mind (ToM) (1.73 ± 0.22; t = 2.04; d = -0.403), jumping to conclusions bias (JTC) (23.3 %; X2 = 0.94; V = 0.178). In recent-onset psychosis, neurocognitive functioning was not related to the history of SB. As novelty, individuals with previous SB showed higher CI. Also, regarding social cognition and metacognition, individuals with prior SB tended to present extremely low externalizing bias, better ToM, and presence of JTC.

A pilot 1-year follow-up randomised controlled trial comparing metacognitive training to psychoeducation in schizophrenia: effects on insight.

Poor insight in schizophrenia spectrum disorders (SSD) is linked with negative outcomes. This single-centre, assessor-blind, parallel-group 1-year follow-up randomised controlled trial (RCT) tested whether metacognitive training (MCT) (compared to psychoeducation) may improve insight and outcomes in outpatients with SSD assessed: at baseline (T0); after treatment (T1) and at 1-year follow-up (T2). Insight (primary outcome) was measured with (i) the Schedule for Assessment of Insight-Expanded version- (SAI-E), including illness recognition (IR), symptom relabelling (SR), treatment compliance (TC) and total insight scores (TIS); and (ii) the Beck Cognitive Insight Scale (BCIS). Between-group comparisons were nonsignificant, while within the MCT group (but not within controls) there was a significant medium effect size for improved TIS at T2 (d = 0.67, P = 0.02). Secondary outcomes included cognitive measures: Jumping to Conclusions (JTC), Theory of Mind (ToM), plus symptom severity and functioning. Compared to psychoeducation, MCT improved the PANSS excitement (d = 1.21, P = 0.01) and depressed (d = 0.76, P = 0.05) factors at T2; and a JTC task both at T1 (P = 0.016) and at T2 (P = 0.031). Participants in this RCT receiving MCT showed improved insight at 1-year follow-up, which was associated with better mood and reduced JTC cognitive bias. In this pilot study, no significant benefits on insight of MCT over psychoeducation were detected, which may have been due to insufficient power.

Impact of 3-Monthly Long-Acting Injectable Paliperidone Palmitate in Schizophrenia: A Retrospective, Real-World Analysis of Population-Based Health Records in Spain.

BACKGROUND: Treatment of schizophrenia requires long-term medication to prevent relapse. Treatment nonadherence may increase the risk of relapse, leading to increased hospitalizations and emergency room (ER) visits. Long-acting injectables (LAIs) such as paliperidone palmitate have improved treatment adherence and therefore symptoms. However, real-world studies comparing 3-monthly LAI formulations with other LAIs and oral antipsychotics (OAs) are scarce. OBJECTIVE: The objective of this study was to investigate and evaluate the clinical effectiveness of paliperidone palmitate LAI monthly (PP1M; Xeplion®) and 3-monthly (PP3M; Trevicta®) formulations compared with the monthly LAI aripiprazole (AM; Abilify Maintena®) and OAs in Spain. METHODS: This was a retrospective, observational study including 2275 adult patients with schizophrenia in a Spanish population. Data from hospital, primary care, and pharmacy dispensation electronic medical records were obtained between January 2017 and February 2018. The main outcomes included psychiatric hospitalizations and ER visit rates, days on treatment, and treatment persistence. RESULTS: Patients receiving PP3M had a significantly lower mean hospitalization rate (0.00046 ± standard deviation [SD] 0.00181; p < 0.0001) than other treatment groups. Kaplan-Meier curves revealed that 92.0 and 88.4% of patients receiving PP3M remained hospitalization free by 12 and 18 months, respectively. All treatment groups had at least a twofold significantly higher risk of psychiatric hospitalizations compared with those receiving PP3M or OAs, and the hospitalization risk among the PP3M group was significantly lower (hazard ratio [HR] 0.46; 95% confidence interval [CI] 0.31-0.67). The risk of ER visits was significantly lower with both PP3M and PP1M than with OAs, and lowest with PP3M (HR 0.462 [95% CI 0.29-0.62] and HR 0.833 [95% CI 0.59-0.97], respectively). Time until treatment switch with PP3M was high, with more than 86.5% of patients remaining on treatment at 18 months. CONCLUSIONS: PP3M was more effective than OAs and monthly LAIs in improving clinical outcomes for patients with schizophrenia in a real-world setting in Spain.

Investigating the Role of Insight, Decision-Making and Mentalizing in Functional Outcome in Schizophrenia: A Cross-Sectional Study.

BACKGROUND: Recovery has become a priority in schizophrenia spectrum disorders (SSDs). This study aimed to investigate predictors of objective-general functioning and disability-and subjective-quality of life (QoL)-measures of functional outcomes in SSD. METHODS: Sample: n = 77 SSD outpatients (age 18-64, IQ > 70) participating in a randomised controlled trial. Baseline data were used to build three multivariable linear regression models on: (i) general functioning-General Assessment of Functioning (GAF); (ii) disability-the World Health Organization Disability Assessment Schedule (WHODAS-2.0); and (iii) QoL-Satisfaction Life Domains Scale (SLDS). RESULTS: Young age and being employed (R2 change = 0.211; p = 0.001), late adolescence premorbid adjustment (R2 change = 0.049; p = 0.0050), negative symptoms and disorganization (R2 change = 0.087; p = 0.025) and Theory of Mind (R2 change = 0.066, p = 0.053) predicted general functioning. Previous suicidal behaviour (R2 change = 0.068; p = 0.023) and negative and depressive symptoms (R2 change = 0.167; p = 0.001) were linked with disability. Previous suicidal behaviour (R2 change = 0.070, p = 0.026), depressive symptoms (R2 change = 0.157; p < 0.001) and illness recognition (R2 change = 0.046, p = 0.044) predicted QoL. CONCLUSIONS: Negative, disorganization and depressive symptoms, older age, unemployment, poor premorbid adjustment, previous suicide attempts and illness awareness appear to underlie a poor global functional outcome in SSD. Achieving recovery in SSD appears to require both symptomatic remission (e.g., through antipsychotics) and measures to improve mastery and relieve low mood.

Investigating the Contribution of Decision-Making, Cognitive Insight, and Theory of Mind in Insight in Schizophrenia: A Cross-Sectional Study.

INTRODUCTION: Insight in schizophrenia spectrum disorders (SSD) is associated with outcomes. Although the neurocognitive basis of insight is widely accepted, the specific contribution of decision-making (Jumping to Conclusions [JTC]), Cognitive Insight (CI), and Theory of Mind (ToM) to insight remains unclear. METHODS: The sample included N = 77 SSD outpatients aged 18-64 years from a randomized controlled trial of metacognitive training. Assessments included JTC-Beads Task, CI-Beck Cognitive Insight Scale, ToM-Hinting Task, and the Emotions Recognition Test Faces. STATISTICS: hierarchical multivariable linear regression models tested their contribution to total insight (TI) and three insight dimensions - illness recognition (IR), symptom relabelling (SR), and treatment compliance (TC) - measured with the Schedule for the Assessment of Insight - Expanded version, whilst adjusting for potential confounders. RESULTS: Bivariate analyses showed that CI was associated with TI (R2 change = 0.214; p < 0.001), IR (R2 change = 0.154; p = 0.003), and SR (R2 change = 0.168; p = 0.003), while JTC predicted IR (R2 change = 0.790; p = 0.020). Multivariable regression models showed that CI predicted TI (R2 change = 0.116; p = 0.036) and SR (R2 change = 0.166, p = 0.011), whereas JTC was linked with IR (R2 change = 0.710; p = 0.026). ToM was not linked with any insight score. No cognitive variable was associated with treatment compliance. DISCUSSION: Results supported the (meta)cognitive model of insight in SSD. JTC and CI emerged as the main (meta)cognitive processes underlying insight. Metacognitive interventions may therefore improve insight in SSD, although these therapies alone may fail to address treatment compliance.

Use of Ecological Momentary Assessment Through a Passive Smartphone-Based App (eB2) by Patients With Schizophrenia: Acceptability Study.

BACKGROUND: Ecological momentary assessment (EMA) tools appear to be useful interventions for collecting real-time data on patients' behavior and functioning. However, concerns have been voiced regarding the acceptability of EMA among patients with schizophrenia and the factors influencing EMA acceptability. OBJECTIVE: The aim of this study was to investigate the acceptability of a passive smartphone-based EMA app, evidence-based behavior (eB2), among patients with schizophrenia spectrum disorders and the putative variables underlying their acceptance. METHODS: The participants in this study were from an ongoing randomized controlled trial (RCT) of metacognitive training, consisting of outpatients with schizophrenia spectrum disorders (F20-29 of 10th revision of the International Statistical Classification of Diseases and Related Health Problems), aged 18-64 years, none of whom received any financial compensation. Those who consented to installation of the eB2 app (users) were compared with those who did not (nonusers) in sociodemographic, clinical, premorbid adjustment, neurocognitive, psychopathological, insight, and metacognitive variables. A multivariable binary logistic regression tested the influence of the above (independent) variables on "being user versus nonuser" (acceptability), which was the main outcome measure. RESULTS: Out of the 77 RCT participants, 24 (31%) consented to installing eB2, which remained installed till the end of the study (median follow-up 14.50 weeks) in 14 participants (70%). Users were younger and had a higher education level, better premorbid adjustment, better executive function (according to the Trail Making Test), and higher cognitive insight levels (measured with the Beck Cognitive Insight Scale) than nonusers (univariate analyses) although only age (OR 0.93, 95% CI 0.86-0.99; P=.048) and early adolescence premorbid adjustment (OR 0.75, 95% CI 0.61-0.93; P=.01) survived the multivariable regression model, thus predicting eB2 acceptability. CONCLUSIONS: Acceptability of a passive smartphone-based EMA app among participants with schizophrenia spectrum disorders in this RCT where no participant received financial compensation was, as expected, relatively low, and linked with being young and good premorbid adjustment. Further research should examine how to increase EMA acceptability in patients with schizophrenia spectrum disorders, in particular, older participants and those with poor premorbid adjustment. TRIAL REGISTRATION: ClinicalTrials.gov NCT04104347; https://clinicaltrials.gov/ct2/show/NCT04104347.

Jumping to conclusions and suicidal behavior in depression and psychosis.

Suicidal behavior (SB) involves an impairment in decision-making (DM). Jumping to conclusions bias (JTC), described as the tendency to make hasty decisions based on insufficient information, could be considered as analogous of impaired DM. However, the link between JTC and SB in psychosis and other diagnoses (e.g., depression) has never been studied. This study aims to explore the presence of JTC and SB in a sample comprising 121 patients with psychosis and 101 with depression. Sociodemographic and clinical data were collected, including history of SB and symptom-severity scores. JTC was assessed by the beads task, and patients who reached decisions with the second bead or before were considered to exhibit JTC. Age, gender, diagnosis, educational level, symptom severity, substance use, and SB were compared according to JTC presence. Variables found to be significantly different in this comparison were included in a multivariate analysis. JTC was more prevalent in patients with depression than with psychosis: 55.6% in an 85:15 ratio and 64.6% in a 60:40 ratio. When multivariate logistic regression was applied to study the influence of diagnosis (psychosis versus depression), age, and SB, only SB remained statistically significant (OR 2.05; 95% CI 0.99-4.22; p = 0.05). The population studied was assembled by grouping different samples from previous research, and we have not included control variables such as other clinical variables, neurocognitive measurements, or personality traits. JTC may be more closely linked to SB, as a transdiagnostic variable, rather than to a specific diagnosis.

Early intervention services, patterns of prescription and rates of discontinuation of antipsychotic treatment in first-episode psychosis.

AIMS: Non-compliance is still an important problem in psychotic patients. Although antipsychotic (AP) treatment leads to a decrease in psychotic relapses, there are no clear recommendations about how long treatment should be maintained after first-episode psychosis (FEP) and no indication of the rates and causes of treatment withdrawal in this group. METHODS: We evaluated a large sample of patients with FEP for 2 years to compare the time to all-cause treatment discontinuation of AP drugs and the time to the first relapse. We collected the sociodemographic and psychopathological characteristics of the sample. The number of relapses was also recorded. RESULTS: A total of 310 FEP patients were assessed across seven early intervention teams (mean age = 30.2 years; SD = 11.2). The most prevalent diagnosis at baseline was psychotic disorder not otherwise specified (36.1%), and the most commonly used APs were risperidone (26.5%) and olanzapine (18.7%). A lack of efficacy was the most frequent reason for the withdrawal of the first AP prescribed, followed by non-compliance. There were no differences in the relapse rates between different APs. Patients treated with long-acting injectable (LAI) APs presented less disengagement from services than patients treated with oral APs. CONCLUSIONS: Although there were no differences between the different APs in terms of relapse rates, LAIs had higher retention rates than oral APs in early intervention services. Compliance is still an important issue in Psychiatry, so clinicians should use different strategies to encourage it, such as the use of LAI treatments.

Can metacognitive interventions improve insight in schizophrenia spectrum disorders? A systematic review and meta-analysis.

BACKGROUND: Patients with schizophrenia spectrum disorders (SSD) tend to lack insight, which is linked to poor outcomes. The effect size of previous treatments on insight changes in SSD has been small. Metacognitive interventions may improve insight in SSD, although this remains unproved. METHODS: We carried out a systematic review and meta-analysis of randomized controlled trials (RCTs) to examine the effects of metacognitive interventions designed for SSD, namely Metacognitive Training (MCT) and Metacognitive Reflection and Insight Therapy (MERIT), on changes in cognitive and clinical insight at post-treatment and at follow-up. RESULTS: Twelve RCTs, including 10 MCT RCTs (n = 717 participants) and two MERIT trials (n = 90), were selected, totalling N = 807 participants. Regarding cognitive insight six RCTs (n = 443) highlighted a medium effect of MCT on self-reflectiveness at post-treatment, d = 0.46, p < 0.01, and at follow-up, d = 0.30, p < 0.01. There was a small effect of MCT on self-certainty at post-treatment, d = -0.23, p = 0.03, but not at follow-up. MCT was superior to controls on an overall Composite Index of cognitive insight at post-treatment, d = 1.11, p < 0.01, and at follow-up, d = 0.86, p = 0.03, although we found evidence of heterogeneity. Of five MCT trials on clinical insight (n = 244 participants), which could not be meta-analysed, four of them favoured MCT compared v. control. The two MERIT trials reported conflicting results. CONCLUSIONS: Metacognitive interventions, particularly Metacognitive Training, appear to improve insight in patients with SSD, especially cognitive insight shortly after treatment. Further long-term RCTs are needed to establish whether these metacognitive interventions-related insight changes are sustained over a longer time period and result in better outcomes.

Study protocol of a randomised clinical trial testing whether metacognitive training can improve insight and clinical outcomes in schizophrenia.

BACKGROUND: Although insight in schizophrenia spectrum disorders (SSD) has been associated with positive outcomes, the effect size of previous treatments on insight has been relatively small to date. The metacognitive basis of insight suggests that metacognitive training (MCT) may improve insight and clinical outcomes in SSD, although this remains to be established. METHODS: This single-center, assessor-blind, parallel-group, randomised clinical trial (RCT) aims to investigate the efficacy of MCT for improving insight (primary outcome), including clinical and cognitive insight, which will be measured by the Schedule for Assessment of Insight (Expanded version) (SAI-E) and the Beck Cognitive Scale (BCIS), respectively, in (at least) n = 126 outpatients with SSD at three points in time: i) at baseline (T0); ii) after treatment (T1) and iii) at 1-year follow-up (T2). SSD patients receiving MCT and controls attending a non-intervention support group will be compared on insight level changes and several clinical and cognitive secondary outcomes at T1 and T2, whilst adjusting for baseline data. Ecological momentary assessment (EMA) will be piloted to assess functioning in a subsample of participants. DISCUSSION: To the best of our knowledge, this will be the first RCT testing the effect of group MCT on multiple insight dimensions (as primary outcome) in a sample of unselected patients with SSD, including several secondary outcomes of clinical relevance, namely symptom severity, functioning, which will also be evaluated with EMA, hospitalizations and suicidal behaviour. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04104347. Date of registration: 26/09/2019 (Retrospectively registered).