Clinical progression during psychosis has been closely associated with grey matter abnormalities resulting from atypical brain development. However, the complex interplay between psychopathology and heterogeneous maturational trajectories challenges the identification of neuroanatomical features that anticipate symptomatic decline.

To investigate cortical volume longitudinal deviations in first-episode psychosis (FEP) using normative modelling, exploring their relationship with long-term cognitive and symptomatic outcomes, as well as their cytoarchitectural and neurobiological underpinnings.

We collected magnetic resonance imaging (MRI), cognitive and symptomatic data from 195 healthy controls and 357 drug-naïve or minimally medicated FEP individuals that were followed up 1, 3, 5 and 10 years following the first episode (1209 MRI scans and assessments in total). Using normative modelling, we derived subject-specific centile scores for cortical volume to investigate atypical deviations in FEP and their relationship to long-term cognitive and symptomatic deterioration. The resulting centile association maps were further characterised by examining their cytoarchitectural and neurobiological attributes using normative atlases.

FEP centiles demonstrated a widespread reduction at treatment initiation, with longitudinal analysis showing an increase during treatment time, indicating convergence towards normal maturation trajectories. Interestingly, this effect was reduced in highly medicated individuals. Additionally, we found that cognitive impairments experienced during early FEP stages worsened under long-term medication. Positive symptomatology was negatively associated with regional centiles, and individuals with higher centiles benefited most from treatment. Cytoarchitectural and neurobiological analyses revealed that regional centiles related to FEP, as well as to symptomatology, were associated with specific molecular features, such as regional serotonin and dopamine receptor densities.

Collectively, these findings underscore the potential use of centile-based normative modelling for a better understanding of how atypical cortical development contributes to the long-term clinical progression of neurodevelopmental conditions.

Suicide represents a significant public health concern. Suicide prevention strategies are shifting toward transdiagnostic perspectives examining interrelated risk factors, but their interrelationships remain unclear. This study investigated relationships between psychopathological dimensions, impulsivity, and childhood maltreatment in individuals with suicidal ideation (SI), comparing those with versus without intention to act using network analysis.

Data were obtained from the Suicide Prevention and Intervention Study project. Participants were categorized into two groups based on their intention to act according to the Columbia Suicide Severity Rating Scale. Psychological symptoms, impulsivity traits, and childhood maltreatment were assessed. Network analysis was performed, and centrality measures were computed.

A total of 1,265 individuals were categorized into the SI without intention to act (n = 345) and SI with intention to act (n = 920) groups. The former showed lower depression and hostility scores, and lower prevalence of major depressive and anxiety disorders. Network analyses revealed that in the SI without intention to act group, obsessive-compulsive symptoms were central, connecting to depression and anxiety, while negatively correlating with non-planning impulsivity. In contrast, the SI with intention to act group showed a more densely interconnected network where emotional abuse served as a bridge between childhood maltreatment and other psychopathological dimensions.

This study identifies symptom interaction patterns between individuals with SI without and with intention to act. Understanding these relationships may improve suicide risk assessment and inform personalized interventions, potentially reducing the transition from ideation to action. Trauma-focused approaches addressing emotional abuse may be especially relevant for individuals at high risk.

Insight assessment in psychosis remains challenging in practice-oriented research.

To develop and validate a proxy measure for insight based on information from electronic health records (EHR). For that purpose, we used data on the Scale to Assess Unawareness of Mental Disorder (SUMD) and data from EHR notes of patients in an early psychosis intervention programme (Programa de Atención a Fases Iniciales de Psicosis, Santander, Spain).

Junior and senior clinicians examined 134 clinical notes from 106 patients to explore criterion and content validity between SUMD and a clinician-rated proxy measure, using three SUMD items.

In terms of criterion validity, SUMD scores correlated with the proxy (r = 0.61, P < 0.001), even after adjusting for the following confounders: type of psychotic disorder, clinical remission status and rater experience (r = 0.58, P < 0.001); and the proxy predicted good insight status (odds ratio 20.95, 95% CI 7.32–59.91, P < 0.001). Regarding content validity, the three main SUMD subscores correlated with the proxy (r = 0.55–0.60, P < 0.005). There were no significant differences in age, gender or other clinical variables, i.e. discriminant validity, and the proxy significantly correlated with validated psychometric instruments, i.e. external validity. Intraclass correlation coefficient (i.e. interrater reliability) was 0.88 (95% CI 0.59–1.00, P < 0.05).

This SUMD-based proxy measure was shown to have good to excellent validity and reliability, which may offer a reliable and efficient alternative for assessing insight in real-world clinical practice, EHR-based research and management. Future studies should explore its applicability across different healthcare contexts and its potential for automation, using natural language-processing techniques.

Adolescents are at a heightened risk of suicide reattempts following hospital discharge, but few evidence-based interventions exist. This study evaluated the efficacy of the self-awareness of mental health (SAM) program combined with treatment as usual (TAU) versus TAU alone in reducing reattempts among high-risk adolescents.

A randomized clinical trial was conducted across nine Spanish hospitals (January 2021–March 2024) with 261 adolescents (12–17 years) who had attempted suicide within the last 15 days. Participants were assigned to SAM + TAU (n=128) or TAU (n=133), with 12-month follow-up. The primary outcome was suicide reattempts within 12 months; secondary analyses examined time to reattempt and associated risk factors.

After 12-months, no significant differences were found in reattempt rates [22.6% (SAM) versus 27.8% (TAU); OR=0.610, 95%CI (0.321–1.151), p=0.127] or time to reattempt [HR=0.606, 95%CI (0.390–1.021), p=0.060]. In SAM, attentional impulsivity emerged as a significant risk factor [HR=1.126, 95% CI (1.004–1.263), p=0.043], while nonplanning impulsivity was protective [HR=0.878, 95%CI (0.814–0.948), p<0.001]. In TAU, increased suicide risk was linked to suicidal intentionality [HR=1.341, 95%CI (1.009–1.782), p=0.044] and more prior attempts [HR=1.230, 95%CI (1.039–1.457), p=0.016]. Conversely, fewer psychiatric diagnoses emerged as a protective factor [HR=0.821, 95%CI (0.677–0.996), p=0.045].

While no significant differences were found between groups, SAM identified important psychological factors influencing suicide risk. These findings provide a foundation for targeted interventions to prevent reattempts in adolescents.

Predicting long-term outcome trajectories in psychosis remains a crucial and challenging goal in clinical practice. The identification of reliable neuroimaging markers has often been hindered by the clinical and biological heterogeneity of psychotic disorders and the limitations of traditional case-control methodologies, which often mask individual variability. Recently, normative brain charts derived from extensive magnetic resonance imaging (MRI) data-sets covering the human lifespan have emerged as a promising biologically driven solution, offering a more individualised approach.

To examine how deviations from normative cortical and subcortical grey matter volume (GMV) at first-episode psychosis (FEP) onset relate to symptom and functional trajectories.

We leveraged the largest available brain normative model (N > 100 000) to explore normative deviations in a sample of over 240 patients with schizophrenia spectrum disorders who underwent MRI scans at the onset of FEP and received clinical follow-up at 1, 3 and 10 years.

Our findings reveal that deviations in regional normative GMV at FEP onset are significantly linked to overall long-term clinical trajectories, modulating the effect of time on both symptom and functional outcome. Specifically, negative deviations in the left superior temporal gyrus and Broca’s area at FEP onset were notably associated with a more severe progression of positive and negative symptoms, as well as with functioning trajectories over time.

These results underscore the potential of brain developmental normative approaches for the early prediction of disorder progression, and provide valuable insights for the development of preventive and personalised therapeutic strategies.

Recent changes in US government priorities have serious negative implications for science that will compromise the integrity of mental health research, which focuses on vulnerable populations. Therefore, as editors of mental science journals and custodians of the academic record, we confirm with conviction our collective commitment to communicating the truth.

One of the most relevant risk factors for suicide is the presence of previous attempts. The symptomatic profile of people who reattempt suicide deserves attention. Network analysis is a promising tool to study this field.

To analyze the symptomatic network of patients who have attempted suicide recently and compare networks of people with several attempts and people with just one at baseline.

1043 adult participants from the Spanish cohort “SURVIVE” were part of this study. Participants were classified into two groups: single attempt group (n = 390) and reattempt group (n = 653). Different network analyses were carried out to study the relationships between suicidal ideation, behavior, psychiatric symptoms, diagnoses, childhood trauma, and impulsivity. A general network and one for each subgroup were estimated.

People with several suicide attempts at baseline scored significantly higher across all clinical scales. The symptomatic networks were equivalent in both groups of patients (p > .05). Although there were no overall differences between the networks, some nodes were more relevant according to group belonging.

People with a history of previous attempts have greater psychiatric symptom severity but the relationships between risk factors show the same structure when compared with the single attempt group. All risk factors deserve attention regardless of the number of attempts, but assessments can be adjusted to better monitor the occurrence of reattempts.

There is a lack of standardised psychometric data in electronic health record (EHR)-based research. Proxy measures of symptom severity based on patients' clinical records may be useful surrogates in mental health EHR research.

This study aimed to validate proxy tools for the short versions of the Positive and Negative Syndrome Scale (PANSS-6), Young Mania Rating Scale (YMRS-6) and Montgomery–Åsberg Depression Rating Scale (MADRS-6).

A cross-sectional, multicentre study was conducted in a sample of 116 patients with first-episode psychosis from 12 public hospitals in Spain. Concordance between PANSS-6, YMRS-6 and MADRS-6 scores and their respective proxies was evaluated based on information from EHR clinical notes, using a variety of statistical procedures, including multivariate tests to adjust for potential confounders. Bootstrapping techniques were used for internal validation, and an independent cohort from the Treatment and Early Intervention in Psychosis Program (TIPP-Lausanne, Switzerland) for external validation.

The proxy versions correlated strongly with their respective standardised scales (partial correlations ranged from 0.75 to 0.84) and had good accuracy and discriminatory power in distinguishing between patients in and not in remission (percentage of patients correctly classified ranged from 83.9 to 91.4% and bootstrapped optimism-corrected area under the receiver operating characteristic curve ranged from 0.76 to 0.89), with high interrater reliability (intraclass correlation coefficient of 0.81). The findings remained robust in the external validation data-set.

The proxy instruments proposed for assessing psychotic and affective symptoms by reviewing EHR provide a feasible and reliable alternative to traditional structured psychometric procedures, and a promising methodology for real-world practice settings.

Individuals with a first episode of psychosis (FEP) show rapid weight gain during the first months of treatment, which is associated with a reduction in general physical health. Although genetics is assumed to be a significant contributor to weight gain, its exact role is unknown.

We assembled a population-based FEP cohort of 381 individuals that was split into a Training (n = 224) set and a Validation (n = 157) set to calculate the polygenic risk score (PRS) in a two-step process. In parallel, we obtained reference genome-wide association studies for body mass index (BMI) and schizophrenia (SCZ) to examine the pleiotropic landscape between the two traits. BMI PRSs were added to linear models that included sociodemographic and clinical variables to predict BMI increase (∆BMI) in the Validation set.

The results confirmed considerable shared genetic susceptibility for the two traits involving 449 near-independent genomic loci. The inclusion of BMI PRSs significantly improved the prediction of ∆BMI at 12 months after the onset of antipsychotic treatment by 49.4% compared to a clinical model. In addition, we demonstrated that the PRS containing pleiotropic information between BMI and SCZ predicted ∆BMI better at 3 (12.2%) and 12 months (53.2%).

We prove for the first time that genetic factors play a key role in determining ∆BMI during the FEP. This finding has important clinical implications for the early identification of individuals most vulnerable to weight gain and highlights the importance of examining genetic pleiotropy in the context of medically important comorbidities for predicting future outcomes.

Understanding the evolution of negative symptoms in first-episode psychosis (FEP) requires long-term longitudinal study designs that capture the progression of this condition and the associated brain changes.

To explore the factors underlying negative symptoms and their association with long-term abnormal brain trajectories.

We followed up 357 people with FEP over a 10-year period. Factor analyses were conducted to explore negative symptom dimensionality. Latent growth mixture modelling (LGMM) was used to identify the latent classes. Analysis of variance (ANOVA) was conducted to investigate developmental trajectories of cortical thickness. Finally, the resulting ANOVA maps were correlated with a wide set of regional molecular profiles derived from public databases.

Three trajectories (stable, decreasing and increasing) were found in each of the three factors (expressivity, experiential and attention) identified by the factor analyses. Patients with an increasing trajectory in the expressivity factor showed cortical thinning in caudal middle frontal, pars triangularis, rostral middle frontal and superior frontal regions from the third to the tenth year after the onset of the psychotic disorder. The F-statistic map of cortical thickness expressivity differences was associated with a receptor density map derived from positron emission tomography data.

Stable and decreasing were the most common trajectories. Additionally, cortical thickness abnormalities found at relatively late stages of FEP onset could be exploited as a biomarker of poor symptom outcome in the expressivity dimension. Finally, the brain areas with less density of receptors spatially overlap areas that discriminate the trajectories of the expressivity dimension.

Cognitive reserve (CR) has been associated with the development and prognosis of psychosis. Different proxies have been used to estimate CR among individuals. A composite score of these proxies could elucidate the role of CR at illness onset on the variability of clinical and neurocognitive outcomes.

Premorbid intelligence quotient (IQ), years of education and premorbid adjustment were explored as proxies of CR in a large sample (N = 424) of first-episode psychosis (FEP) non-affective patients. Clusters of patients were identified and compared based on premorbid, clinical and neurocognitive variables at baseline. Additionally, the clusters were compared at 3-year (N = 362) and 10-year (N = 150) follow-ups.

The FEP patients were grouped into five CR clusters: C1 (low premorbid IQ, low education and poor premorbid) 14%; C2 (low premorbid IQ, low education and good premorbid adjustment) 29%; C3 (normal premorbid IQ, low education and poor premorbid adjustment) 17%; C4 (normal premorbid IQ, medium education and good premorbid adjustment) 25%; and C5 (normal premorbid IQ, higher education and good premorbid adjustment) 15%. In general, positive and negative symptoms were more severe in the FEP patients with the lowest CR at baseline and follow-up assessments, while those with high CR presented and maintained higher levels of cognitive functioning.

CR could be considered a key factor at illness onset and a moderator of outcomes in FEP patients. A high CR could function as a protective factor against cognitive impairment and severe symptomatology. Clinical interventions focused on increasing CR and documenting long-term benefits are interesting and desirable.

It is unclear what the prevalence of metabolic syndrome (MetS) in drug-naïve first-episode of psychosis (FEP) is, as previous meta-analyses were conducted in minimally exposed or drug-naïve FEP patients with psychotic disorder at any stage of the disease; thus, a meta-analysis examining MetS in naïve FEP compared with the general population is needed.

Studies on individuals with FEP defined as drug-naïve (0 days exposure to antipsychotics) were included to conduct a systematic review. A meta-analysis of proportions for the prevalence of MetS in antipsychotic-naïve patients was performed. Prevalence estimates and 95% CI were calculated using a random-effect model. Subgroup analyses and meta-regressions to identify sources and the amount of heterogeneity were also conducted.

The search yielded 4143 articles. After the removal of duplicates, 2473 abstracts and titles were screened. At the full-text stage, 112 were screened, 18 articles were included in a systematic review and 13 articles in the main statistical analysis. The prevalence of MetS in naïve (0 days) FEP is 13.2% (95% CI 8.7–19.0). Ethnicity accounted for 3% of the heterogeneity between studies, and diagnostic criteria used for MetS accounted for 7%. When compared with controls matched by sex and age, the odds ratio is 2.52 (95% CI 1.29–5.07; p = 0.007).

Our findings of increased rates of MetS in naïve FEP patients suggest that we are underestimating cardiovascular risk in this population, especially in those of non-Caucasian origin. Our findings support that altered metabolic parameters in FEPs are not exclusively due to antipsychotic treatments.

Lower levels of education have been associated with the development of psychosis. Investigating educational achievement in the first episode of psychosis (FEP) patients may shed light on the origins of the alterations and on the variability of outcomes in psychotic disorders.

Education achievement was explored in a large sample (n = 659) of FEP patients enrolled in programa de atención a fases iniciales de psicosis (PAFIP), a research and assistance program conducted in Spain. Patients were stratified according to the Spanish educational system according to their attendance in primary (low), secondary (medium) or university studies (high). The three groups were compared on available premorbid, clinical and neuropsychological variables. A subgroup of patients (n = 209), comprising the 10-year follow-up PAFIP cohort, were again compared.

Overall, 49% and 37% of FEP patients had low and medium levels of education, respectively. In total, 13% of the patients with a higher level of education were more frequently women (64%) and older at illness onset (36 years old), reported better premorbid adjustment, presented less severe positive symptoms and better functioning; and showed higher premorbid intelligence quotient and better performance on all the explored cognitive domains. Ten years later the FEP patients in the medium- and high-education groups had good global functioning and a neurocognitive performance within the normal limits.

Higher education is associated with better initial conditions and more favourable outcomes after an FEP. Sharing this information with the world's educational systems is essential to targeting resources and designing innovative programs or strategies to compensate for student difficulties.

A large body of research states that cognitive impairment in schizophrenia is static. Nevertheless, most previous studies lack a control group or have small study samples or short follow-up periods.

We aimed to address these limitations by studying a large epidemiological cohort of patients with first-episode schizophrenia spectrum disorders and a comparable control sample for a 10-year period.

Our results support the generalized stability of cognitive functions in schizophrenia spectrum disorders considering the entire group. However, the existence of a subgroup of patients characterized by deteriorating cognition and worse long-term clinical outcomes must be noted. Nevertheless, it was not possible to identify concomitant factors or predictors of deterioration (all Ps > 0.05).

Cognitive functions in schizophrenia spectrum disorder are stable; however, a subgroup of subjects that deteriorate can be characterized.

Little is known about changes in brain functioning after first-episode psychosis (FEP). Such knowledge is important for predicting the course of disease and adapting interventions. Functional magnetic resonance imaging has become a promising tool for exploring brain function at the time of symptom onset and at follow-up.

A systematic review of longitudinal fMRI studies with FEP patients according to PRISMA guidelines. Resting-state and task-activated studies were considered together.

Eleven studies were included. These reported on a total of 236 FEP patients were evaluated by two fMRI scans and clinical assessments. Five studies found hypoactivation at baseline in prefrontal cortex areas, two studies found hypoactivation in the amygdala and hippocampus, and three others found hypoactivation in the basal ganglia. Other hypoactivated areas were the anterior cingulate cortex, thalamus and posterior cingulate cortex. Ten out of eleven studies reported (partial) normalization by increased activation after antipsychotic treatment. A minority of studies observed hyperactivation at baseline.

This review of longitudinal FEP samples studies reveals a pattern of predominantly hypoactivation in several brain areas at baseline that may normalize to a certain extent after treatment. The results should be interpreted with caution given the small number of studies and their methodological and clinical heterogeneity.

The duration of untreated psychosis (DUP) has been associated with negative outcomes in psychosis; however, few studies have focused on the duration of active psychotic symptoms after commencing treatment (DAT). In this study, we aimed to evaluate the effect of DUP and DAT on functional long-term outcomes (3 years) in patients with early psychosis.

We evaluated the Scale for the Assessment of Positive Symptoms (SAPS) at frequent intervals for 3 years after presentation to determine the DAT for 307 individuals with first-episode psychosis together with DUP and clinical variables. The functional outcomes were assessed using the Disability Assessment Scale (DAS) at three years, and functional recovery was defined as minimal impairment and return to activity. Associated variables, DAT and DUP were included in logistic regression models to predict functional outcomes. Receiver operating characteristic curves and Youden’s index were applied to assess the best cut-off values.

DAT, (Wald: 13.974; ExpB: 1.097; p < 0.001), premorbid adjustment, initial BPRS score, gender, age of onset and schizophrenia diagnosis were significant predictors of social functioning, whereas only premorbid adjustment (Wald: 11.383; ExpB:1.009), DAT (Wald: 4.850; ExpB: 1.058; p = 0.028) and education were significant predictors of recovery. The optimal cut-off of DAT for predicting social functioning was 3.17 months for DAT (sensitivity: 0.68; specificity: 0.64; Youden’s index: 0.314).

DAT is strongly related to functional outcomes independent of the DUP period or other variables. As a modifiable variable, the reduction of the DAT should be considered a main focus of intervention from the onset of the illness to improve long-term outcomes.

Neuroanatomical abnormalities in first-episode psychosis (FEP) tend to be subtle and widespread. The vast majority of previous studies have used small samples, and therefore may have been underpowered. In addition, most studies have examined participants at a single research site, and therefore the results may be specific to the local sample investigated. Consequently, the findings reported in the existing literature are highly heterogeneous. This study aimed to overcome these issues by testing for neuroanatomical abnormalities in individuals with FEP that are expressed consistently across several independent samples.

Structural Magnetic Resonance Imaging data were acquired from a total of 572 FEP and 502 age and gender comparable healthy controls at five sites. Voxel-based morphometry was used to investigate differences in grey matter volume (GMV) between the two groups. Statistical inferences were made at p < 0.05 after family-wise error correction for multiple comparisons.

FEP showed a widespread pattern of decreased GMV in fronto-temporal, insular and occipital regions bilaterally; these decreases were not dependent on anti-psychotic medication. The region with the most pronounced decrease – gyrus rectus – was negatively correlated with the severity of positive and negative symptoms.

This study identified a consistent pattern of fronto-temporal, insular and occipital abnormalities in five independent FEP samples; furthermore, the extent of these alterations is dependent on the severity of symptoms and duration of illness. This provides evidence for reliable neuroanatomical alternations in FEP, expressed above and beyond site-related differences in anti-psychotic medication, scanning parameters and recruitment criteria.

The aim of the current study was to examine the heterogeneity of functional outcomes in first episode psychosis (FEP) patients and related clinical, neurocognitive and sociodemographic factors using a cluster analytic approach.

A large sample of FEP patients (N = 209) was functionally reassessed 10 years after the first contact with an early intervention service. Multiple baseline, 3-year and 10-year follow-up variables were explored.

The cluster analysis emphasized the existence of six independent clusters of functioning: one cluster was normal overall (42.16%), two clusters showed moderate interpersonal (9.63%) or instrumental (12.65%) deficits, two clusters showed more severe interpersonal (12.05%) or interpersonal and instrumental (13.85%) deficits and there was a significantly overall impaired cluster (9.63%). Cluster comparisons showed that several baseline and follow-up factors were differentially involved in functional outcomes.

The current study demonstrated that distinct clusters of functioning in FEP patients can be identified. The fact that a variety of profiles was observed contributes to a better understanding of the nature of the heterogeneity characterizing FEP patients and has clinical implications for developing individualized treatment plans.