Suicidal thoughts and behaviors (STBs) are a major concern in people with psychotic disorders. There is a need to examine their prevalence over long-term follow-up after first-episode psychosis (FEP) and determine their early predictors.

Of 510 participants with FEP evaluated on 26 risk factors for later outcomes, 260 were reassessed after 21 years of follow-up for lifetime ratings of most severe suicidal ideation, number of suicide attempts, and lethality of the most severe attempt. Risk factors and STB outcomes were modeled using hierarchical linear regression analysis.

Over the 21-year follow-up period, 62.7% of participants experienced suicidal thoughts, 40.8% attempted suicide, and 18 died of suicide (3.5% case fatality and 20.6% proportionate mortality). Suicidal ideation was independently predicted by parental socioeconomic status, familial load of major depression, neurodevelopmental delay, poor adolescence social networks, and suicidal thoughts/behavior at FEP. The number of suicide attempts was independently predicted by years of follow-up, familial load of major depression, obstetric complications, childhood adversity, and suicidal thoughts/behavior at FEP. Lethality was independently predicted by familial load of major depression, obstetric complications, neurodevelopmental delay, and poor adolescence social networks. The proportion of variance in suicidal ideation, attempts, and lethality explained by the independent predictors was 29.3%, 21.2%, and 18.1%, respectively.

STBs are highly prevalent in psychotic disorders and leads to substantial morbidity and mortality. They were predicted by a number of early risk factors, whose clinical recognition should contribute to improved prediction and prevention in people with psychotic disorders.

Few studies have examined the long-term outcomes of first-episode psychosis (FEP) among patients beyond symptomatic and functional remission. This study aimed to broaden the scope of outcome indicators by examining the relationships between 12 outcomes of FEP patients at 20.9 years after their initial diagnosis.

At follow-up, 220 out of 550 original patients underwent a new assessment. Twelve outcomes were assessed via semistructured interviews and complementary scales: symptom severity, functional impairment, personal recovery, social disadvantage, physical health, number of suicide attempts, number of episodes, current drug use, dose-years of antipsychotics (DYAps), cognitive impairment, motor abnormalities, and DSM-5 final diagnosis. The relationships between these outcome measures were investigated using Spearman’s correlation analysis and exploratory factor analysis, while the specific connections between outcomes were ascertained using network analysis.

The outcomes were significantly correlated; specifically, symptom severity, functioning, and personal recovery showed the strongest correlations. Exploratory factor analysis of the 12 outcomes revealed two factors, with 11 of the 12 outcomes loading on the first factor. Network analysis revealed that symptom severity, functioning, social disadvantage, diagnosis, cognitive impairment, DYAps, and number of episodes were the most interconnected outcomes.

Network analysis provided new insights into the heterogeneity between outcomes among patients with FEP. By considering outcomes beyond symptom severity, the rich net of interconnections elucidated herein can facilitate the development of interventions that target potentially modifiable outcomes and generalize their impact on the most interconnected outcomes.

Evidence suggests a possible relationship between exposure to childhood adversity (CA) and functional impairment in psychosis. However, the impact of CA on long-term outcomes of psychotic disorders remains poorly understood.

Two hundred and forty-three patients were assessed at their first episode of psychosis for CA and re-assessed after a mean of 21 years of follow-up for several outcome domains, including symptoms, functioning, quality of life, cognitive performance, neurological dysfunction, and comorbidity. The unique predictive ability of CA exposure for outcomes was examined using linear regression analysis controlling for relevant confounders, including socioeconomic status, family risk of schizophrenia, and obstetric complications.

There were 54% of the patients with a documented history of CA at mild or higher levels. CA experiences were more prevalent and severe in schizophrenia than in other psychotic disorders (p < 0.001). Large to very large effect sizes were observed for CA predicting most role functioning variables and negative symptoms (ΔR2 between 0.105 and 0.181). Moderate effect sizes were observed for positive symptoms, personal functioning, impaired social cognition, impaired immediate verbal learning, poor global cognition, internalized stigma, poor personal recovery, and drug abuse severity (ΔR2 between 0.040 and 0.066). A dose–response relationship was observed between levels of CA and severity of outcome domains.

Our results suggest a strong and widespread link between early adversity exposure and outcomes of psychotic disorders. Awareness of the serious long-term consequences of CA should encourage better identification of those at risk and the development of effective interventions.

First-episode psychotic disorders comprise a heterogeneous phenotype with a complex etiology involving numerous common small-effect genetic variations and a wide range of environmental exposures. We examined whether a family of schizophrenia spectrum disorder (FH-Sz) interacts with an environmental risk score (ERS-Sz) regarding the outcome of patients with non-affective first episode psychosis (NAFEP).

We included 288 patients with NAFEP who were evaluated after discharge from an intensive 2-year program. We evaluated three outcome measures: symptomatic remission, psychosocial functioning, and personal recovery. We analyzed the main and joint associations of a FH-Sz and the ERS-Sz on the outcomes by using the relative excess risk due to interaction (RERI) approach.

A FH-Sz showed a significant association with poor symptomatic remission and psychosocial functioning outcomes, although there was no significant interaction between a FH-Sz and the ERS-Sz on these outcomes. The ERS-Sz did not show a significant association with poor symptomatic remission and psychosocial functioning outcomes, even though the magnitude of the interaction between ERS-Sz and FH-Sz with the later outcome was moderate (RERI = 6.89, 95% confidence interval −16.03 to 29.81). There was no association between a FH-Sz and the ERS-Sz and personal recovery.

Our results provide further empirical support regarding the contribution of FH-Sz to poor symptomatic remission and poor psychosocial functioning outcomes in patients with NAFEP.

Polygenic risk scores for educational attainment (PRSEA), cognitive reserve (CR), and clinical symptoms are associated with functioning in first-episode psychosis (FEP). Nevertheless, the mechanisms underlying their complex interaction are yet to be explored. This study assessed the mediating role of CR and clinical symptoms, both negative (NS) and positive (PS), on the interrelationship between PRSEA and functionality, one year after a FEP.

A total of 162 FEP patients underwent clinical, functional, and genetic assessments. Using genome-wide association study summary results, PRSEA were constructed for each individual. Two mediation models were performed. The parallel mediation model explored the relationship of PRSEA with functionality through CR and clinical symptoms. The serial mediation model tested a causal chain of the three mediators: CR, NS, and PS. Mediation analysis was performed using the PROCESS function V.4.1 in SPSS V.22.

A serial mediation model revealed a causal chain for PRSEA > CR > NS > Functionality (β = −0.35, 95%CI [−0.85, −0.04], p < 0.05). The model fit the data satisfactorily (CFI = 1.00; RMSEA = 0.00; SRMR = 7.2 × 10−7). Conversely, no parallel mediation was found between the three mediators, PRSEA and functionality and the model poorly fit the data (CFI = 0.30; RMSEA = 0.25; SRMR = 0.11).

Both CR and NS mediate the relationship between PRSEA and functionality at one-year follow-up, using serial mediation analysis. This may be relevant for prevention and personalized early intervention to reduce illness impact and improve functional outcomes in FEP patients.

Patients with a first episode of psychosis (FEP) display clinical, cognitive, and structural brain abnormalities at illness onset. Ventricular enlargement has been identified in schizophrenia since the initial development of neuroimaging techniques. Obstetric abnormalities have been associated with an increased risk of developing psychosis but also with cognitive impairment and brain structure abnormalities. Difficulties during delivery are associated with a higher risk of birth asphyxia leading to brain structural abnormalities, such as ventriculomegaly, which has been related to cognitive disturbances.

We examined differences in ventricular size between 142 FEP patients and 123 healthy control participants using magnetic resonance imaging. Obstetric complications were evaluated using the Lewis–Murray scale. We examined the impact of obstetric difficulties during delivery on ventricle size as well as the possible relationship between ventricle size and cognitive impairment in both groups.

FEP patients displayed significantly larger third ventricle size compared with healthy controls. Third ventricle enlargement was associated with diagnosis (higher volume in patients), with difficulties during delivery (higher volume in subjects with difficulties), and was highest in patients with difficulties during delivery. Verbal memory was significantly associated with third ventricle to brain ratio.

Our results suggest that difficulties during delivery might be significant contributors to the ventricular enlargement historically described in schizophrenia. Thus, obstetric complications may contribute to the development of psychosis through changes in brain architecture.

Although diagnostic instability in first-episode psychosis (FEP) is of major concern, little is known about its determinants. This very long-term follow-up study aimed to examine the diagnostic stability of FEP diagnoses, the baseline predictors of diagnostic change and the timing of diagnostic change.

This was a longitudinal and naturalistic study of 243 subjects with FEP who were assessed at baseline and reassessed after a mean follow-up of 21 years. The diagnostic stability of DSM-5 psychotic disorders was examined using prospective and retrospective consistencies, logistic regression was used to establish the predictors of diagnostic change, and survival analysis was used to compare time to diagnostic change across diagnostic categories.

The overall diagnostic stability was 47.7%. Schizophrenia and bipolar disorder were the most stable diagnoses, with other categories having low stability. Predictors of diagnostic change to schizophrenia included a family history of schizophrenia, obstetric complications, developmental delay, poor premorbid functioning in several domains, long duration of untreated continuous psychosis, spontaneous dyskinesia, lack of psychosocial stressors, longer duration of index admission, and poor early treatment response. Most of these variables also predicted diagnostic change to bipolar disorder but in the opposite direction and with lesser effect sizes. There were no significant differences between specific diagnoses regarding time to diagnostic change. At 10-year follow-up, around 80% of the diagnoses had changed.

FEP diagnoses other than schizophrenia or bipolar disorder should be considered as provisional. Considering baseline predictors of diagnostic change may help to enhance diagnostic accuracy and guide therapeutic interventions.

Clinical intervention in early stages of psychotic disorders is crucial for the prevention of severe symptomatology trajectories and poor outcomes. Genetic variability is studied as a promising modulator of prognosis, thus novel approaches considering the polygenic nature of these complex phenotypes are required to unravel the mechanisms underlying the early progression of the disorder.

The sample comprised of 233 first-episode psychosis (FEP) subjects with clinical and cognitive data assessed periodically for a 2-year period and 150 matched controls. Polygenic risk scores (PRSs) for schizophrenia, bipolar disorder, depression, education attainment and cognitive performance were used to assess the genetic risk of FEP and to characterize their association with premorbid, baseline and progression of clinical and cognitive status.

Schizophrenia, bipolar disorder and cognitive performance PRSs were associated with an increased risk of FEP [false discovery rate (FDR) ⩽ 0.027]. In FEP patients, increased cognitive PRSs were found for FEP patients with more cognitive reserve (FDR ⩽ 0.037). PRSs reflecting a genetic liability for improved cognition were associated with a better course of symptoms, functionality and working memory (FDR ⩽ 0.039). Moreover, the PRS of depression was associated with a worse trajectory of the executive function and the general cognitive status (FDR ⩽ 0.001).

Our study provides novel evidence of the polygenic bases of psychosis and its clinical manifestation in its first stage. The consistent effect of cognitive PRSs on the early clinical progression suggests that the mechanisms underlying the psychotic episode and its severity could be partially independent.

Functional impairment is a defining feature of psychotic disorders. A range of factors has been shown to influence functioning, including negative symptoms, cognitive performance and cognitive reserve (CR). However, it is not clear how these variables may affect functioning in first-episode psychosis (FEP) patients. This 2-year follow-up study aimed to explore the possible mediating effects of CR on the relationship between cognitive performance or specific clinical symptoms and functional outcome.

A prospective study of non-affective FEP patients was performed (211 at baseline and 139 at follow-up). CR was entered in a path analysis model as potential mediators between cognitive domains or clinical symptoms and functioning.

At baseline, the relationship between clinical variables or cognitive performance and functioning was not mediated by CR. At follow-up, the effect of attention (p = 0.003) and negative symptoms (p = 0.012) assessed at baseline on functioning was partially mediated by CR (p = 0.032 and 0.016), whereas the relationship between verbal memory (p = 0.057) and functioning was mediated by CR (p = 0.014). Verbal memory and positive and total subscales of PANSS assessed at follow-up were partially mediated by CR and the effect of working memory on functioning was totally mediated by CR.

Our results showed the influence of CR in mediating the relationship between cognitive domains or clinical symptoms and functioning in FEP. In particular, CR partially mediated the relationship between some cognitive domains or clinical symptoms and functioning at follow-up. Therefore, CR could improve our understanding of the long-term functioning of patients with a non-affective FEP.

Previous literature supports antipsychotics’ (AP) efficacy in acute first-episode psychosis (FEP) in terms of symptomatology and functioning but also a cognitive detrimental effect. However, regarding functional recovery in stabilised patients, these effects are not clear. Therefore, the main aim of this study is to investigate dopaminergic/anticholinergic burden of (AP) on psychosocial functioning in FEP. We also examined whether cognitive impairment may mediate these effects on functioning.

A total of 157 FEP participants were assessed at study entry, and at 2 months and 2 years after remission of the acute episode. The primary outcomes were social functioning as measured by the functioning assessment short test (FAST). Cognitive domains were assessed as potential mediators. Dopaminergic and anticholinergic AP burden on 2-year psychosocial functioning [measured with chlorpromazine (CPZ) and drug burden index] were independent variables. Secondary outcomes were clinical and socio-demographic variables.

Mediation analysis found a statistical but not meaningful contribution of dopaminergic receptor blockade burden to worse functioning mediated by cognition (for every 600 CPZ equivalent points, 2-year FAST score increased 1.38 points). Regarding verbal memory and attention, there was an indirect effect of CPZ burden on FAST (b = 0.0045, 95% CI 0.0011–0.0091) and (b = 0.0026, 95% CI 0.0001–0.0006) respectively. However, only verbal memory post hoc analyses showed a significant indirect effect (b = 0.009, 95% CI 0.033–0.0151) adding premorbid IQ as covariate. We did not find significant results for anticholinergic burden.

CPZ dose effect over functioning is mediated by verbal memory but this association appears barely relevant.

Motor abnormalities (MAs) are the primary manifestations of schizophrenia. However, the extent to which MAs are related to alterations of subcortical structures remains understudied.

We aimed to investigate the associations of MAs and basal ganglia abnormalities in first-episode psychosis (FEP) and healthy controls. Magnetic resonance imaging was performed on 48 right-handed FEP and 23 age-, gender-, handedness-, and educational attainment-matched controls, to obtain basal ganglia shape analysis, diffusion tensor imaging techniques (fractional anisotropy and mean diffusivity), and relaxometry (R2*) to estimate iron load. A comprehensive motor battery was applied including the assessment of parkinsonism, catatonic signs, and neurological soft signs (NSS). A fully automated model-based segmentation algorithm on 1.5T MRI anatomical images and accurate corregistration of diffusion and T2* volumes and R2* was used.

FEP patients showed significant local atrophic changes in left globus pallidus nucleus regarding controls. Hypertrophic changes in left-side caudate were associated with higher scores in sensory integration, and in right accumbens with tremor subscale. FEP patients showed lower fractional anisotropy measures than controls but no significant differences regarding mean diffusivity and iron load of basal ganglia. However, iron load in left basal ganglia and right accumbens correlated significantly with higher extrapyramidal and motor coordination signs in FEP patients.

Taken together, iron load in left basal ganglia may have a role in the emergence of extrapyramidal signs and NSS of FEP patients and in consequence in the pathophysiology of psychosis.

Cognitive deficits are a core feature of early stages in schizophrenia. However, the extent to which antipsychotic (AP) have a deleterious effect on cognitive performance remains under debate. We aim to investigate whether anticholinergic loadings and dose of AP drugs in first episode of psychosis (FEP) in advanced phase of remission are associated with cognitive impairment and the differences between premorbid intellectual quotient (IQ) subgroups.

Two hundred and sixty-six patients participated. The primary outcomes were cognitive dimensions, dopaminergic/anticholinergic load of AP [in chlorpromazine equivalents (Eq-CPZ) and the Anticholinergic Risk Scale (ARS), respectively].

Impairments in processing speed, verbal memory and global cognition were significantly associated with high Eq-CPZ and verbal impairment with high ARS score. Moreover, this effect was higher in the low IQ subgroup.

Clinicians should be aware of the potential cognitive impairment associated with AP in advanced remission FEP, particularly in lower premorbid IQ patients.

Cognitive impairment in schizophrenia-spectrum disorders is highly prevalent and notably influences functional outcomes.

To characterise the cognitive effectiveness of second-generation antipsychotic drugs.

One hundred consecutive and previously unmedicated patients with first-episode schizophrenia-spectrum disorders were admitted. Seventy-seven completed baseline, 1-month and 6-month psychopathological and neuropsychological assessments. Patients were randomised to risperidone or olanzapine treatment. Four final treatment allocation groups were defined since patients continued treatment in their normal setting: risperidone, olanzapine, mixed and no-antipsychotic groups.

There were no differences in cognitive effectiveness between the four treatment groups. Reliable change index methods demonstrated that nearly a half of patients showed an improvement in Global Cognitive Score at the 6-month assessment. Improvement on the neuropsychological tests ranged from 17 to 54%.

A strong predictor of cognitive response was poor performance on baseline neuropsychological tests; response was moderately influenced by a low premorbid scholastic performance and IQ.

Cognitive improvement related to second-generation antipsychotic drugs appeared within the first 4 weeks of treatment and persisted at 6 months irrespective of treatment group. Greater cognitive dysfunction at baseline and lower premorbid cognitive background predicted cognitive improvement in our sample.

Many patients suffering from psychosis are unaware of their disorder and symptoms.

To investigate whether insight changes with time, and how it relates to patients' psychopathology, and to examine the correlations between insight scales in patients with psychoses.

Seventy-five consecutively admitted in-patients with schizophrenia, affective disorder with psychotic symptoms, or schizoaffective disorder were examined after remission of an acute episode and at follow-up (>6 months). Three different scales were used to assess insight.

To some extent, insight into past episodes improved over time in patients with psychosis, regardless of diagnosis. Few significant relationships between insight and psychopathology remained stable at follow-up. The higher the negative and disorganisation dimensions at baseline, the less did attitudes to treatment vary when tested at follow-up. No predictive value for variability of psychopathological dimensions was found for insight dimensions. The insight scales used were highly intercorrelated, suggesting that they measure the same construct.

Insight and psychopathology seem to be semi-independent domains.

Despite the lack of consistent empirical support, modern diagnostic criteria of schizophrenia give particular emphasis to Schneider's first-rank symptoms (FRSs).

To examine the diagnostic significance of FRSs for schizophrenia by trying to overcome the limitations of previous studies.

This study examined the diagnostic accuracy of FRSs for schizophrenia in 660 in-patients with the full spectrum of functional psychotic disorders. Schizophrenia was diagnosed according to three criteria: DSM–III–R broad, DSM–III–R narrow and Feighner, the latter being considered as the gold standard because it does not give particular emphasis to FRSs.

FRSs were highly prevalent in both schizophrenia and non-schizophrenic psychoses. The likelihood ratios (and 95% Cl) of one or more FRSs for Feighner, DSM–III–R narrow and DSM–III–R broad schizophrenia were 1.06 (0.94–1.20), 1.23 (1.09–1.39) and 1.73 (1.44–2.08), respectively. These data indicate that FRSs do not significantly increase the likelihood of having schizophrenia.

FRSs are not useful in differentiating schizophrenia from other psychotic disorders. Diagnostic systems for schizophrenia that are heavily based on these symptoms may arise from a tautological definition of the disorder.

The aim was an investigation of the symptom composition of the negative syndrome of schizophrenia.

A hundred schizophrenic patients were assessed with various rating scales for positive and negative symptoms and typological criteria. A subgroup with a negative syndrome was defined, and a discriminant analysis performed using symptoms from the Scale for the Assessment of Negative Symptoms (SANS) as discriminant variables.

The discriminant function classified 92% of patients correctly. All but four SANS symptoms (inappropriate affect, both attentional items and blocking) were significantly correlated with the discriminant function.

With the exception of some items, the SANS seems to capture adequately the negative syndrome of schizophrenia.