Early Phases Of Schizophrenia Research Articles

Neural dysfunction underlying working memory processing at different stages of the illness course in schizophrenia: a comparative meta-analysis.

Schizophrenia, as a chronic and persistent disorder, exhibits working memory deficits across various stages of the disorder, yet the neural mechanisms underlying these deficits remain elusive with inconsistent neuroimaging findings. We aimed to compare the brain functional changes of working memory in patients at different stages: clinical high risk, first-episode psychosis, and long-term schizophrenia, using meta-analyses of functional magnetic resonance imaging studies. Following a systematic literature search, 56 whole-brain task-based functional magnetic resonance imaging studies (15 for clinical high risk, 16 for first-episode psychosis, and 25 for long-term schizophrenia) were included. The separate and pooled neurofunctional mechanisms among clinical high risk, first-episode psychosis, and long-term schizophrenia were generated by Seed-based d Mapping toolbox. The clinical high risk and first-episode psychosis groups exhibited overlapping hypoactivation in the right inferior parietal lobule, right middle frontal gyrus, and left superior parietal lobule, indicating key lesion sites in the early phase of schizophrenia. Individuals with first-episode psychosis showed lower activation in left inferior parietal lobule than those with long-term schizophrenia, reflecting a possible recovery process or more neural inefficiency. We concluded that SCZ represent as a continuum in the early stage of illness progression, while the neural bases are inversely changed with the development of illness course to long-term course.

Effectiveness of video-based psychiatric rehabilitation for patients with early-phase schizophrenia spectrum: A randomized controlled trial.

This study aimed to establish a comprehensive set of recovery-oriented rehabilitation programs for individuals with schizophrenia, comparing the efficacy of video-based rehabilitation to traditional face-to-face interventions. The primary objective was to assess whether video-based rehabilitation could serve as a viable alternative for individuals with schizophrenia residing in remote areas. A randomized controlled study was used to recruit 80 patients with schizophrenia in a stable post-hospitalization stage following discharge. Participants were categorized into three groups: 24 in the control group, 21 in the face-to-face group, and 35 in the remote group. Assessment parameters included psychiatric symptoms, social skills, family function and self-stigma. A total of 68 participants completed the program. The findings indicated significant differences (p < .05) between the control group and intervention group, particularly in the Positive and Negative Syndrome Scale (PANSS) and the Personal and Social Performance Scale (PSP). The rehabilitation program, tailored for patients in the early phase of the schizophrenia spectrum, demonstrates both effectiveness and feasibility in enhancing clinical symptoms and social functions. Notably, interventions conducted via video proved to be equally effective as those administered face-to-face.

Exercise behaviours and motivation after a first psychotic episode: A digital intervention.

Research has demonstrated that participation in aerobic exercise can have significant beneficial effects across both physical and mental health domains for individuals who are in the early phase of schizophrenia. Despite these notable benefits of exercise, deficits in motivation and a lack of methods to increase engagement are significant barriers for exercise participation, limiting these potentially positive effects. Fortunately, digital health tools have the potential to improve adherence to an exercise program. The present study examined the role of motivation for exercise and the effects of an automated digital text messaging program on participation in an aerobic exercise program. A total of 46 first-episode psychosis participants from an ongoing 12-month randomized clinical trial (Enhancing Cognitive Training through Exercise Following a First Schizophrenia Episode (CT&E-RCT)) were included in an analysis to examine the efficacy of motivational text messaging. Personalized motivational text message reminders were sent to participants with the aim of increasing engagement in the exercise program. We found that participants with higher levels of intrinsic motivation to participate in a text messaging program and in an exercise intervention completed a higher proportion of individual, at-home exercise sessions. In a between groups analysis, participants who received motivational text messages, compared to those who did not, completed a higher proportion of at-home exercise sessions. These results indicate the importance of considering a person's level of motivation for exercise and the potential utility of using individualized and interactive mobile text messaging reminders to increase engagement in aerobic exercise in the early phase of psychosis. We emphasize the need for understanding how individualized patient preferences and needs interplay between intrinsic motivation and digital health interventions for young adults.

Delphi panel to obtain clinical consensus about using long-acting injectable antipsychotics to treat first-episode and early-phase schizophrenia: treatment goals and approaches to functional recovery

BackgroundSchizophrenia is mostly a chronic disorder whose symptoms include psychosis, negative symptoms and cognitive dysfunction. Poor adherence is common and related relapse can impair outcomes. Long-acting injectable antipsychotics (LAIs) may promote treatment adherence and decrease the likelihood of relapse and rehospitalization. Using LAIs in first-episode psychosis (FEP) and early-phase (EP) schizophrenia patients could benefit them, yet LAIs have traditionally been reserved for chronic patients.MethodsA three-step modified Delphi panel process was used to obtain expert consensus on using LAIs with FEP and EP schizophrenia patients. A literature review and input from a steering committee of five experts in psychiatry were used to develop statements about patient population, adverse event management, and functional recovery. Recruited Delphi process psychiatrists rated the extent of their agreement with the statements over three rounds (Round 1: paper survey, 1:1 interview; Rounds 2–3: email survey). Analysis rules determined whether a statement progressed to the next round and the level of agreement deemed consensus. Measures of central tendency (mode, mean) and variability (interquartile range) were reported back to help panelists assess their previous responses in the context of those of the overall group.ResultsThe Delphi panelists were 17 psychiatrists experienced in treating schizophrenia with LAIs, practicing in seven countries (France, Italy, US, Germany, Spain, Denmark, UK). Panelists were presented with 73 statements spanning three categories: patient population; medication dosage, management, and adverse events; and functional recovery domains and assessment. Fifty-five statements achieved ≥ 80% agreement (considered consensus). Statements with low agreement (40-79%) or very low agreement (< 39%) concerned initiating dosage in FEP and EP patients, and managing loss of efficacy and breakthrough episodes, reflecting current evidence gaps. The panel emphasized benefits of LAIs in FEP and EP patients, with consensus that LAIs can decrease the risk of relapse, rehospitalization, and functional dysfunction. The panel supported links between these benefits and multidimensional longer-term functional recovery beyond symptomatic remission.ConclusionsFindings from this Delphi panel support the use of LAIs in FEP and EP schizophrenia patients regardless of disease severity, number of relapses, or social support status. Gaps in clinician knowledge make generating evidence on using LAIs in FEP and EP patients critical.

Weight Gain and Metabolic Changes in Patients With First-Episode Psychosis or Early-Phase Schizophrenia Treated With Olanzapine: A Meta-Analysis.

Patients with first-episode psychosis or early-phase schizophrenia are susceptible to olanzapine-associated weight gain and cardiometabolic dysregulation. This meta-analysis characterized weight and metabolic effects observed during olanzapine treatment in randomized clinical trials in this vulnerable patient population. PubMed, EMBASE, and Dialog were searched for randomized controlled trials (RCTs) reporting weight or cardiometabolic outcomes associated with olanzapine treatment in first-episode psychosis or early-phase schizophrenia. Random-effects meta-analysis and meta-regression were conducted using R v4.0.5. Of 1203 records identified, 26 RCTs informed the analyses. The meta-analytic mean (95% CI) weight gain was 7.53 (6.42-8.63) kg in studies (n = 19) that reported weight gain with olanzapine treatment. Stratified by duration, the mean (95% CI) weight gain was significantly higher in studies >13 weeks in duration than in those lasting ≤13 weeks: 11.35 (10.05-12.65) vs 5.51 (4.73-6.28) kg, respectively. Despite between-study variability, increases from baseline in most glycemic and lipid parameters were generally small in studies of both ≤13 and >13 weeks. There were no correlations, however, between weight gain and metabolic parameter changes when stratified by study duration. In RCTs enrolling patients with first-episode psychosis or early-phase schizophrenia, olanzapine was consistently associated with weight gain that was greater in studies lasting >13 weeks compared with those of ≤13 weeks. Metabolic changes observed across studies suggest that RCTs may underestimate metabolic sequelae vs real-world treatment observations. Patients with first-episode psychosis or early-phase schizophrenia are vulnerable to olanzapine-associated weight gain; strategies minimizing olanzapine-associated weight gain should be carefully considered.

Inter-relationships among psychopathology, cognition, and real-life functioning in early and late phase schizophrenia: A network analysis approach.

Many illness-related factors contribute to the reduction of the real-life functioning observed in people with schizophrenia (SZ). These include the psychopathological dimensions of the disorder such as positive, negative, disorganization, and depressive symptoms as well as impairment in neurocognition, social cognition, and metacognition. The associations between some of these variables change with the duration of illness (DOI), but this aspect was not explored with a network approach. This study aimed at describing and comparing the inter-relationships between psychopathological, cognitive, and functioning variables in early (DOI≤5years) and late (DOI>5years) phase SZ with network analyses and at assessing which variables were more strictly and directly associated with the real-life functioning. A network representation of the relationships between variables and the calculation of centrality indices were performed within each group. The two groups were compared with a network comparison test. Seventy-five patients with early and ninety-two with late phase SZ were included. No differences in the global network structure and strength were found between the two groups. In both groups, visual learning and disorganization exhibited high centrality indices and disorganization, negative symptoms, and metacognition were directly and strongly associated with real-life functioning. In conclusion, regardless of the DOI, a rehabilitation aimed at improving visual learning and disorganization (i.e., the most central variables) might reduce the strength of the associations that compose the network and therefore indirectly facilitate functional recovery. Simultaneously, therapeutic interventions targeting disorganization and metacognition might directly improve real-life functioning.

Treatment Journey From Diagnosis to the Successful Implementation of a Long-Acting Injectable Antipsychotic Agent in Young Adults With Schizophrenia.

Objective: Long-acting injectable antipsychotic agents (LAIs) are effective in schizophrenia relapse prevention but are often underutilized. This study aims to understand treatment patterns leading to a successful LAI implementation following schizophrenia diagnosis in a large dataset that included commercially insured patients in the United States.Methods: Patients aged 18-40 years with a first schizophrenia diagnosis (per ICD-9 or ICD-10 criteria), successful second-generation LAI implementation (defined a priori as ≥ 90 consecutive days of use), and ≥ 1 second-generation oral antipsychotic agent (OA) were identified from IBM MarketScan Commercial and Medicare Supplemental databases from January 1, 2012, to December 31, 2019. Outcomes were measured descriptively.Results: Of 41,391 patients with newly diagnosed schizophrenia, 1,836 (4%) received ≥ 1 LAI; 202 (< 1%) met eligibility criteria of successful LAI implementation following ≥ 1 second-generation OA. Median (range) time between diagnosis and first LAI was 289.5 (0-2,171) days, time between LAI initiation and successful implementation was 90.0 (90-1,061) days, and time to LAI discontinuation after successful implementation was 166.5 (91-799) days. Before LAI initiation, 58% received ≥ 2 OAs. For 86% with successful LAI implementation, the implementation was accomplished with the first LAI.Conclusions: In this dataset of mainly commercially insured patients, LAI use in early-phase schizophrenia was very low (4%). For the majority for whom a LAI was successfully implemented per a priori definition, the implementation was accomplished with the first LAI and in a short period of time (90 days). However, even when LAIs were used in early-phase schizophrenia, they were generally not the first therapy, as most patients had several prior OA treatments.

Prevention in Practice: Improving Communication on the Benefits of Treatments for Schizophrenia

AbstractIntroductionAntipsychotic treatment can help improve outcomes in schizophrenia by reducing the risk of relapse and psychiatric hospitalization, and increasing rates of remission and recovery, particularly when used early in the disease course. However, adherence to oral antipsychotics is often poor. Long-acting injectable (LAI) antipsychotic formulations are associated with significant improvements in treatment adherence compared with oral medications, but LAIs are not widely used in early-phase schizophrenia.MethodsAn educational training program, called “Prevention in Practice,” was developed to offer clinicians a range of innovative, web-based, patient-centered resources, including virtual role-play and educational films, that aim to improve communication between clinicians and patients and help progress care for patients with early-phase schizophrenia. The program was based on findings from the PRELAPSE study, in which clinicians received training to improve communication with patients. The PRELAPSE trial was a cluster randomized study conducted in 39 mental health centers across 19 US states. Sites were randomized to encourage treatment with the LAI aripiprazole once-monthly 400 mg (AOM 400) or to provide treatment as usual. Eligible patients had a diagnosis of schizophrenia, &lt;5 years of lifetime antipsychotic use, and were aged 18–35 years. The objective was to evaluate whether use of the LAI delayed time to first hospitalization in early-phase schizophrenia, compared with usual care. Clinicians received training on the rationale for LAI use in early psychosis, transitioning to LAIs, and discussing LAIs with patients and families. Communication training included the principles of shared decision-making, suggested responses to frequently asked questions, and role-playing.ResultsIn PRELAPSE, the sites randomized to encourage LAI treatment enrolled 234 patients and the sites randomized to usual care enrolled 255 patients. Training clinicians to improve their communication with patients made a difference—91% of patients with early-phase schizophrenia were willing to use LAI treatment at least once in the first 3 months of the study. Furthermore, the results showed that AOM 400 significantly prolonged time to first psychiatric hospitalization compared with usual care (hazard ratio: 0.56 [95% confidence interval: 0.34, 0.92]; p=0.02).ConclusionsOffering clinicians training to improve their communication with patients, through techniques such as shared decision-making and motivational interviewing, may increase LAI use in early-phase schizophrenia. ”Prevention in Practice” is now available in in different countries and languages.FundingOtsuka Pharmaceutical Development &amp; Commercialization, Inc. (Princeton, NJ, USA) and H. Lundbeck A/S (Valby, Denmark).

Delphi Panel on the Dimensions and Assessment of Functional Recovery in First-Episode and Early-Phase Schizophrenia Patients

AbstractFunctional recovery is a treatment goal that goes beyond symptomatic remission and encompasses multiple aspects of schizophrenia patients’ lives, including quality of life, physical, and mental functioning. There is evidence that long-acting injectable (LAI) treatments promote adherence and reduce rehospitalisation and functional decline, which could facilitate patients’ ability to reach functional recovery. Despite this, LAIs are underused in the first-episode (FEP) and early-phase (EP) patient population, due to physician hesitancy and concerns around stigma. A Delphi panel was held to gain expert consensus on an approach to the domains and assessment of functional recovery elements in FEP and EP schizophrenia patients.A literature review and input from a steering committee of 5 experts in psychiatry informed statements development for a three-round modified Delphi process. Round one was conducted via one-to-one video conference interviews, and the successive rounds were conducted via electronic surveys, which enabled international collaboration. Statements on the different domains and assessment for functional recovery were presented to 17 psychiatrists, practicing in 7 countries (France, Italy, US, Germany, Spain, Denmark, and UK), experienced in the treatment of schizophrenia with LAIs. Several analysis rules determined whether a statement could progress to the next round and specified the level of agreement required to achieve consensus. Measures of central tendency (mode, mean) and variability (interquartile range) were reported back to help panelists look at their previous responses in the context of the overall group.A consensus was reached (defined a priori as ≥80% agreement) on all 27 statements covering the dimensions, assessment, and level of achieved functional recovery for FEP and EP patients. The following domains are important to consider when assessing functional recovery: depression, aggressive behaviour, social interaction, family functioning, education/employment, sexual functioning, and leisure activities. Additionally, panellists reached consensus that dimensions should be minimally impairing, if present (excluding sexual functioning) and asked about at every encounter with the patient (excluding sexual functioning and leisure activities). In summary, this Delphi panel yielded agreement that functional recovery is multidimensional and should be assessed regularly as part of usual care on an individual patient level in FEP and EP schizophrenia patients.FundingLundbeck Otsuka Alliance

Delphi Panel on the Relationship Between Long-Acting Injectable Antipsychotics and Longer-Term Functional Recovery in First-Episode and Early-Phase Schizophrenia Patients

AbstractSchizophrenia is among the top ten causes of years lost due to disability. Goals of treatment are evolving beyond remission of psychotic symptoms to include physical and mental functioning, quality of life, and long-term functional recovery. Evidence has shown long-acting injectables (LAIs) are beneficial for schizophrenia patients by increasing treatment adherence and decreasing relapse and rehospitalisation. This potentially reduces disease progression and facilitates functional recovery. However, LAIs are underused and often seen as a last resort for first-episode (FEP) and early-phase (EP) patients, due to physicians’ lack of familiarity and stigma.A three-round modified Delphi panel was held to gain expert consensus on an approach to functional recovery in FEP and EP patients with LAIs. A literature review and input from a steering committee of 5 experts in psychiatry informed the development of statements. Round one was carried out via one-to-one video conference interviews, and the subsequent rounds were conducted via electronic surveys, which enabled international collaboration. Delphi panellists were 17 psychiatrists with schizophrenia treatment experience, practicing in 7 countries (France, Italy, US, Germany, Spain, Denmark, and UK). Several analysis rules determined whether a statement could progress to the next round and specified the level of agreement required to achieve consensus. Measures of central tendencies (mode, mean) and variability (interquartile range) of aggregated responses from the previous round were reported to panelists to understand their response in relation to the group.There was consensus (defined a priori as ≥80% agreement) on the 8 statements relating to long-term treatment goals and LAI links to functional recovery. LAI treatment in FEP and EP patients increases adherence and reduces treatment burden and functional decline compared to the same and other oral medication. Additionally, there was consensus that LAIs lead to better treatment outcome and functional recovery. Other important factors to achieving functional recovery include patient attitude towards treatment and psychoeducation. Furthermore, consensus was reached that functional recovery and quality of life are linked. In summary, this Delphi panel yielded agreement that functional recovery is a reachable goal for FEP and EP patients and can be enhanced using LAIs.FundingLundbeck Otsuka Alliance

Striatum-related spontaneous coactivation patterns predict treatment response on positive symptoms of drug-naive first-episode schizophrenia with risperidone monotherapy.

Evidence from functional magnetic resonance imaging (fMRI) studies of schizophrenia suggests that interindividual variation in the stationary striatal functional circuit may be correlated with antipsychotic treatment response. However, little is known about the role of the dynamic striatum-related network in predicting patients' clinical improvement. The spontaneous coactivation pattern (CAP) technique has recently been found to be important for elucidating the non-stationary nature of functional brain networks. Forty-two drug-naive first-episode schizophrenia patients underwent fMRI and T1W imaging before and after 8 weeks of risperidone monotherapy. The striatum was divided into 3 subregions, including the putamen, pallidum, and caudate. Spontaneous CAPs and CAP states were utilized to measure the dynamic characteristics of brain networks. We used DPARSF and Dynamic Brain Connectome software to analyze each subregion-related CAP and CAP state for each group and then compared the between-group differences in the neural network biomarkers. We used Pearson's correlation analysis to determine the associations between the neuroimaging measurements with between-group differences and the improvement in patients' psychopathological symptoms. In the putamen-related CAPs, patients showed significantly increased intensity in the bilateral thalamus, bilateral supplementary motor areas, bilateral medial, and paracingulate gyrus, left paracentral lobule, left medial superior frontal gyrus, and left anterior cingulate gyrus compared with healthy controls. After treatment, thalamic signals in the putamen-related CAP 1 showed a significant increase, while the signals of the medial and paracingulate gyrus in the putamen-related CAP 3 revealed a significant decrease. The increase in thalamic signal intensity in the putamen-related CAP 1 was significantly and positively correlated with the percentage reduction in PANSS_P. This study is the first to combine striatal CAPs and fMRI to explore treatment response-related biomarkers in the early phase of schizophrenia. Our findings suggest that dynamic changes in CAP states in the putamen-thalamus circuit may be potential biomarkers for predicting patients' variation in the short-term treatment response of positive symptoms.

Predictors for Initiation of Atypical Long-Acting Injectable Antipsychotic Agents in a Commercial Claims Cohort of Individuals With Early-Phase Schizophrenia.

Objective: Long-acting injectable antipsychotic agents (LAIs) have improved clinical effectiveness and adherence versus oral antipsychotic agents (OAs); however, a minority of individuals with schizophrenia are treated with LAIs compared with OAs. This cohort study aimed to evaluate predictors of initiation of atypical LAIs among patients with newly diagnosed schizophrenia in the United States.Methods: Using claims data from IBM MarketScan Commercial and Medicare Supplemental databases between January 1, 2013, and March 31, 2020, adults with first diagnosis of schizophrenia, ≥ 1 OA claim following diagnosis, and continuous benefits were identified. To evaluate predictors of LAI initiation, a Cox proportional hazard regression model per independent predictors and main outcome (ie, LAI initiation) was performed.Results: Of 3,639 patients with early-phase schizophrenia, 369 (10%) had ≥ 1 LAI claim(s) after ≥ 1 OA claim(s). Several factors present prior to LAI initiation were significantly (P < .0001) predictive of LAI initiation: greater monthly OA switches (hazard ratio [95% CI]: 11.39 [7.01-18.51]), unsuccessful OA implementation (3.09 [2.39-3.98]), greater monthly schizophrenia-related hospitalizations (20.83 [14.22-30.51]), and greater monthly schizophrenia-related emergency department visits (4.13 [2.07-8.22]).Conclusions: In this analysis of pharmacy claims records for patients with early-phase schizophrenia, results suggest that LAIs are used less frequently in the early phase than reported in later stages. Their initiation is often reactive to relapse or disease exacerbation, rather than proactive as a relapse-prevention tool for early-phase schizophrenia. These data highlight the underuse of LAIs, particularly in the early phase when they could make the most difference.

Early versus late administration of long-acting injectable antipsychotic agents among patients with newly diagnosed schizophrenia: an analysis of a commercial claims database.

This study was designed to assess healthcare resource utilization (HCRU) and costs in patients with newly diagnosed schizophrenia based on timing and context of long-acting injectable antipsychotic agent (LAI) initiation. Using claims data, patients (aged 18-40 years) with first schizophrenia diagnosis January 2013-September 2019 (index date), no LAI or oral antipsychotic agent claims during 12-month preindex period, and continuous benefit enrollment from 12 months before index date to 12 months after first LAI administration were identified. Patients were grouped based on timing [early (≤1 year after index date) vs. late] and circumstances [reactive (after schizophrenia-related event) vs. proactive] of LAI initiation. Of 1290 patients with at least one LAI claim, 306 met criteria for early ( n = 204; reactive, n = 107; proactive, n = 97) and late ( n = 102; n = 75; n = 27) initiation. HCRU and costs were numerically lower in early versus late groups, and significantly lower for proactive initiation in both groups. Comparing worst-case (late-reactive) and best-case (early-proactive) scenarios, the average annual cost difference was $7195.13 ( P = 0.0233), with major drivers being emergency department ($171.28; P < 0.05) and other outpatient ($2845.73; P < 0.00001) visits. In addition to the clinical advantages previously described in the literature, the proactive use of LAIs in early-phase schizophrenia is associated with lower healthcare costs.

Efficacy of oral versus long-acting antipsychotic treatment in patients with early-phase schizophrenia in Europe and Israel: a large-scale, open-label, randomised trial (EULAST)

Schizophrenia is a severe psychiatric disorder with periods of remission and relapse. As discontinuation of antipsychotic medication is the most important reason for relapse, long-term maintenance treatment is key. Whether intramuscular long-acting (depot) antipsychotics are more efficacious than oral medication in preventing medication discontinuation is still unresolved. We aimed to compare time to all-cause discontinuation in patients randomly allocated to long-acting injectable (LAI) versus oral medication. EULAST was a pragmatic, randomised, open-label trial conducted at 50 general hospitals and psychiatric specialty clinics in 15 European countries and Israel. Patients aged 18 years and older, with DSM-IV schizophrenia (as confirmed by the Mini International Neuropsychiatric Interview 5 plus) and having experienced their first psychotic episode from 6 months to 7 years before screening, were randomly allocated (1:1:1:1) using block randomisation to LAI paliperidone, LAI aripiprazole, or the respective oral formulations of these antipsychotics. Randomisation was stratified by country and duration of illness (6 months up to 3 years vs 4 to 7 years). Patients were followed up for up to 19 months. The primary endpoint was discontinuation, regardless of the reason, during 19 months of treatment. We used survival analysis to assess the time until all-cause discontinuation in the intention-to-treat (ITT) group, and per protocol analyses were also done. This trial is registered with ClinicalTrials.gov, NCT02146547, and is complete. Between Feb 24, 2015, and Dec 15, 2018, 533 individuals were recruited and assessed for eligibility. The ITT population included 511 participants, with 171 (33%) women and 340 (67%) men, and a mean age of 30·5 (SD 9·6) years. 410 (80%) of 511 participants were White, 35 (7%) were Black, 20 (4%) were Asian, and 46 (9%) were other ethnicity. In the combined oral antipsychotics treatment group of 247 patients, 72 (29%) patients completed the study and 175 (71%) met all-cause discontinuation criteria. In the combined LAI treatment arm of 264 patients, 95 (36%) completed the study and 169 (64%) met the all-cause discontinuation criteria. Cox regression analyses showed that treatment discontinuation for any cause did not differ between the two combined treatment groups (hazard ration [HR] 1·16, 95% CI 0·94-1·43, p=0·18). No significant difference was found in the time to all-cause discontinuation between the combined oral and combined LAI treatment groups (log rank test χ2=1·87 [df 1]; p=0·17). During the study, 121 psychiatric hospitalisations occurred in 103 patients, and one patient from each of the LAI groups died; the death of the patient assigned to paliperidone was assessed to be unrelated to the medication, but the cause of other patient's death was not shared with the study team. 86 (25%) of 350 participants with available data met akathisia criteria and 70 (20%) met parkinsonism criteria at some point during the study. We found no substantial advantage for LAI antipsychotic treatment over oral treatment regarding time to discontinuation in patients with early-phase schizophrenia, indicating that there is no reason to prescribe LAIs instead of oral antipsychotics if the goal is to prevent discontinuation of antipsychotic medication in daily clinical practice. Lundbeck and Otsuka.

Lower fractional anisotropy without evidence for neuro-inflammation in patients with early-phase schizophrenia spectrum disorders

Various lines of research suggest immune dysregulation as a potential therapeutic target for negative and cognitive symptoms in schizophrenia spectrum disorders (SSD). Immune dysregulation would lead to higher extracellular free-water (EFW) in cerebral white matter (WM), which may partially underlie the frequently reported lower fractional anisotropy (FA) in SSD. We aim to investigate differences in EFW concentrations – a presumed proxy for neuro-inflammation – between early-phase SSD patients (n = 55) and healthy controls (HC; n = 37), and to explore immunological and cognitive correlates. To increase specificity for EFW, we study several complementary magnetic resonance imaging contrasts that are sensitive to EFW. FA, mean diffusivity (MD), magnetization transfer ratio (MTR), myelin water fraction (MWF) and quantitative T1 and T2 were calculated from diffusion-weighted imaging (DWI), magnetization transfer imaging (MTI) and multicomponent driven equilibrium single-pulse observation of T1/T2 (mcDESPOT). For each measure, WM skeletons were constructed with tract-based spatial statistics. Multivariate SSD-HC comparisons with WM skeletons and their average values (i.e. global WM) were not statistically significant. In voxel-wise analyses, FA was significantly lower in SSD in the genu of the corpus callosum and in the left superior longitudinal fasciculus (p < 0.04). Global WM measures did not correlate with immunological markers (i.e. IL1-RA, IL-6, IL-8, IL-10 and CRP) or cognition in HC and SSD after corrections for multiple comparisons. We confirmed lower FA in early-phase SSD patients. However, nonFA measures did not provide additional evidence for immune dysregulation or for higher EFW as the primary mechanism underlying the reported lower FA values in SSD.

Effectiveness of oral versus long-acting antipsychotic treatment early-phase schizophrenia patients: an open-label randomized trial

IntroductionSchizophrenia is a chronic psychiatric illness with periods of remission and relapse. Patients vary in the frequency and severity of relapse, time until relapse and time in remission. Discontinuation of antipsychotic medication is by far the most important reason for relapse. A possible method to optimize medication adherence is to treat patients with long-term, depot medication rather than oral medication.ObjectivesPrimary objective is to compare all cause discontinuation rates in patients with schizophrenia randomized to either one of the two depot medications (aripiprazole depot or paliperidone palmitate) with patients randomized to either one of the two oral formulations of the same medication (aripiprazole or paliperidone) over an 19 month follow-up period.MethodsPragmatic, randomized, open label, multicenter, multinational comparative trial consisting of a 19 month treatment period. Patients aged 18 years or older, having experienced the first psychosis 1-7 years ago, currently meeting DSM-IV-R criteria for schizophrenia. Patients are randomized 1:1:1:1 to paliperidone palmitate, aripiprazole depot, oral aripiprazole or oral paliperidone. The primary outcome is all cause discontinuation.ResultsIn the Intent to Treat sample (n=511), no difference was found in time to ACD between the combined oral and combined depot treatment arms, nor between the four individual treatment arms.ConclusionsEven though the scientific evidence comparing oral and depot medication has been inconsistent, most studies were conducted in rigorous clinical settings, which may have biased those results. In contract, given the pragmatic, open label design of the current trial, the results may be more representative of common daily practice.DisclosureNo significant relationships.

Predictive Biomarkers for Antipsychotic Treatment Response in Early Phase of Schizophrenia: Multi-Omic Measures Linking Subcortical Covariant Network, Transcriptomic Signatures, and Peripheral Epigenetics.

BackgroundVolumetric alterations of subcortical structures as predictors of antipsychotic treatment response have been previously corroborated, but less is known about whether their morphological covariance relates to treatment outcome and is driven by gene expression and epigenetic modifications.MethodsSubcortical volumetric covariance was analyzed by using baseline T1-weighted magnetic resonance imaging (MRI) in 38 healthy controls and 38 drug-naïve first-episode schizophrenia patients. Patients were treated with 8-week risperidone monotherapy and divided into responder and non-responder groups according to the Remission in Schizophrenia Working Group (RSWG). We utilized partial least squares (PLS) regression to examine the spatial associations between gene expression of subcortical structures from a publicly available transcriptomic dataset and between-group variances of structural covariance. The peripheral DNA methylation (DNAm) status of a gene of interest (GOI), overlapping between genes detected in the PLS and 108 schizophrenia candidate gene loci previously reported, was examined in parallel with MRI scanning.ResultsIn the psychotic symptom dimension, non-responders had a higher baseline structural covariance in the putamen–hippocampus–pallidum–accumbens pathway compared with responders. For disorganized symptoms, significant differences in baseline structural covariant connections were found in the putamen–hippocampus–pallidum–thalamus circuit between the two subgroups. The imaging variances related to psychotic symptom response were spatially related to the expression of genes enriched in neurobiological processes and dopaminergic pathways. The DNAm of GOI demonstrated significant associations with patients’ improvement of psychotic symptoms.ConclusionBaseline subcortical structural covariance and peripheral DNAm may relate to antipsychotic treatment response. Phenotypic variations in subcortical connectome related to psychotic symptom response may be transcriptomically and epigenetically underlaid. This study defines a roadmap for future studies investigating multimodal imaging epigenetic biomarkers for treatment response in schizophrenia.

The effect of serum lipids and short-chain fatty acids on cognitive functioning in drug-naïve, first episode schizophrenia patients

ObjectiveMany studies have reported the important role of serum levels of short-chain fatty acids (SCFAs) in lipid metabolism and cognitive dysfunction. This study investigated the role of plasma lipids and SCFAs on cognitive functioning in drug- naïve first episode schizophrenia. MethodsThis study recruited 44 schizophrenia inpatients and 35 healthy controls. Plasma lipid metabolism was characterized using standard enzymatic methods and an automated analyzer. Serum levels of SCFAs were measured by Gas chromatography mass spectrometry (GC-MS). Cognitive performance was evaluated by the MATRICS Consensus Cognitive Battery (MCCB). ResultsThe patient group showed significantly higher serum levels of total SCFAs, acetic acid, acetic acid/ propionic acid ratio, and poorer cognitive scores compared with the control group (p's < 0.05). Within the patient group, the lipid levels were positively associated with acetic acid/ propionic acid ratio (p's < 0.05). Furthermore, multiple regression analysis revealed that the interactions of LDL level × acetic acid/ propionic acid ratio was a significant predictor of the MCCB working memory, and processing speed subscale scores within the patient group. ConclusionsCognitive dysfunction and abnormal serum levels of SCFAs occur in the early phase of schizophrenia. Lipid metabolism and serum levels of SCFAs might be, both independently or interactively, associated with cognitive dysfunction in schizophrenia.

Clinical and treatment predictors of relapse during a three-year follow-up of a cohort of first episodes of schizophrenia

Relapses are frequent in the first years following a first episode of schizophrenia (FES), being associated with a higher risk of developing a chronic psychotic disorder, and poor clinical and functional outcomes. The identification and intervention over factors associated with relapses in these early phases are timely and relevant.In this study, 119 patients in remission after a FES were closely followed over three years. Participants came from the 2EPS Project, a coordinated, naturalistic, longitudinal study of 15 tertiary centers in Spain. Sociodemographic, clinical, treatment and substance abuse data were analyzed.49.6% of the participants relapsed during the 3-years follow-up. None of the baseline demographic and clinical characteristics analyzed showed a statistically significant association with relapses. 22% of patients that finished the follow-up without relapsing were not taking any antipsychotic. The group that relapsed presented higher mean antipsychotics doses (381.93 vs. 242.29 mg of chlorpromazine equivalent/day, p = 0.028) and higher rates of antipsychotic polytherapy (28.6% vs. 13%, p < 0.001), benzodiazepines use (30.8% vs. 8.5%, p < 0.001), side effects reports (39.2% vs. 25%, p = 0.022), psychological treatment (51.8% vs. 33.9%, p = 0.03), and cannabis consumption (93.2% vs. 56.7%, p < 0.001). Clozapine use was notably higher in the group that reminded in remission (21.7% vs. 8.2%, p < 0.019).These findings may guide clinicians to detect subgroups of patients with higher risk to present a second episode of psychosis, focusing on measures to ensure an adequate treatment or facilitating cannabis use cessation. This study supports future research to identify relapse prevention strategies for patients in early phases of schizophrenia.

Treatment Approaches for First Episode and Early-Phase Schizophrenia in Adolescents and Young Adults: A Delphi Consensus Report from Europe.

PurposeAlthough first-episode psychosis (FEP) in youth, particularly early-onset schizophrenia (EOS), is managed similarly to adult-onset schizophrenia, few antipsychotics are approved for people aged 13–18 years. We aimed to explore areas of uncertainty in EOS management and provide evidence-based recommendations to mental health specialists. We used the Delphi methodology to gain knowledge in areas lacking evidence-based strategies. This standardized methodology consists of the development of a questionnaire by content experts, which is then submitted to a broader panel of professionals (panelists) to survey their level of agreement on the topics proposed.Materials and MethodsThe developed questionnaire covered patient management from diagnosis to maintenance treatment and was administered to a broader panel of specialists across Europe. Based on an analysis of responses received in this first round, the items that needed further insight were submitted to the panel for a second round and then reanalysed.ResultsAn initial set of 90 items was developed; in round I, consensus was reached for 83/90 items (92%), while it was reached for 7/11 (64%) of the items sent out for rerating in round II. Feedback for rounds I and II was obtained from 54/92 and 48/54 approached experts, respectively. There was broad agreement on diagnostic standards, multimodal approaches and focus on adverse events, but uncertainty in terms of pharmacological strategies (including clozapine) in case of failure and antipsychotic dosing in younger patients.ConclusionDespite knowledge about diagnostic clues and integrated management of EOS, this study highlights the lack of standardization in treating EOS, with safety arguments having a major role in the decision-making process. Targeted clinical trials and systematic dissemination across Europe of current scientific evidence on the value of early intervention services is hoped to contribute to standardized and improved quality care for patients with early-phase psychosis and schizophrenia.