Short-term exposure to antipsychotics has proven to be beneficial. However, naturalistic studies are lacking regarding the long-term use of antipsychotics. This study aimed to investigate changes in use of antipsychotics over 20 years after a first-episode schizophrenia.

This study is part of the Danish OPUS trial (1998–2000), including 496 participants with first-episode schizophrenia. Participants were reassessed four times over 20 years. The main outcomes were days on medication, redeemed prescriptions of clozapine, psychiatric hospitalizations, and employment.

At the 20-year follow-up, an attrition of 71% was detected. In total, 143 out of 496 participated, with 36% (n = 51) in remission-of-psychotic-symptoms-off-medication. The lowest number of days on medication (mean [s.d.], 339 [538] days) was observed in this group over 20 years. Register data on redeemed antipsychotics were available for all trial participants (n = 416). Individuals in treatment with antipsychotics (n = 120) at the 20-year follow-up had spent significantly more days in treatment (5405 [1857] v. 1434 [1819] mean days, p = 0.00) and more had ever redeemed a prescription of clozapine (25% v. 7.8%, p = 0.00) than individuals who had discontinued antipsychotics (n = 296). Further, discontinuers had significantly higher employment at the 20-year follow-up (28.4% v. 12.5%, p = 0.00).

In a cohort of individuals with first-episode schizophrenia, 36% were in remission-of-psychotic-symptoms-off-medication. However, high attrition was detected, potentially affecting study results by inflating results from individuals with favorable outcomes. From register data, free from attrition, approximately 30% were in treatment with antipsychotics, and 70% had discontinued antipsychotics. Individuals in treatment had the least favorable outcomes, implying greater illness severity.

We explored the prevalence of autism and attention-deficit hyperactivity disorder in first-episode psychosis. Through service evaluation involving 509 individuals, detailed analyses were conducted on neurodevelopmental traits and patterns of service utilisation.

Prevalence of neurodivergence in first-episode psychosis was 37.7%. Neurodivergent individuals used urgent mental health services more frequently (Mann–Whitney U = 25925, Z = −2.832, P = 0.005) and had longer hospital stays (Mann–Whitney U = 22816, Z = −4.886, P ≤ 0.001) than non-neurodivergent people. Neurodivergent people spend more than twice as long in mental health hospitals at a time than the non-neurodivergent people (Mann–Whitney U = 22 909.5, Z = −4.826, P ≤ 0.001). Mediation analysis underscored indirect impact of neurodivergence on hospital stay durations through age at onset of psychosis and use of emergency services.

Prevalence of neurodevelopmental conditions in first-episode psychosis is underestimated. Neurodivergent individuals show increased utilisation of mental health services and experience psychosis earlier. Early assessment is crucial for optimising psychosis management and improving mental health 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.

The intelligence quotient (IQ) of patients with first-episode psychosis (FEP) and their unaffected relatives may be related to the genetic burden of schizophrenia (SCZ). The polygenic score approach can be useful for testing this question.

To assess the contribution of the polygenic risk scores for SCZ (PGS-SCZ) and polygenic scores for IQ (PGS-IQ) to the individual IQ and its difference from the mean IQ of the family (named family-IQ) through a family-based design in an FEP sample.

The PAFIP-FAMILIES sample (Spain) consists of 122 FEP patients, 131 parents, 94 siblings, and 176 controls. They all completed the WAIS Vocabulary subtest for IQ estimation and provided a DNA sample. We calculated PGS-SCZ and PGS-IQ using the continuous shrinkage method. To account for relatedness in our sample, we performed linear mixed models. We controlled for covariates potentially related to IQ, including age, years of education, sex, and ancestry principal components.

FEP patients significantly deviated from their family-IQ. FEP patients had higher PGS-SCZ than other groups, whereas the relatives had intermediate scores between patients and controls. PGS-IQ did not differ between groups. PGS-SCZ significantly predicted the deviation from family-IQ, whereas PGS-IQ significantly predicted individual IQ.

PGS-SCZ discriminated between different levels of genetic risk for the disorder and was specifically related to patients’ lower IQ in relation to family-IQ. The genetic background of the disorder may affect neurocognition through complex pathological processes interacting with environmental factors that prevent the individual from reaching their familial cognitive potential.

Cognitive deficits are a core feature of schizophrenia and are closely associated with poor functional outcomes. It remains unclear if cognitive deficits progress over time or remain stable. Determining patients at increased risk of progressive worsening might help targeted neurocognitive remediation approaches.

This 20-year follow-up study examined neurocognitive outcomes of 156 participants from the OPUS I trial. Neurocognition was assessed using the brief assessment of cognition in schizophrenia at the 10- and 20-year follow-up, allowing us to examine changes in neurocognition over ten years.

We found that 30.5% of patients had a declining course of neurocognition, 49.2% had a stable course of neurocognition and 20.3% experienced improvements in neurocognition. Good cognitive functioning at the 20-year follow-up was significantly associated with higher levels of social functioning (B 6.86, CI 4.71–9.02, p < 0.001) while increasing experiential negative symptoms were significantly correlated to cognitive worsening (PC-0.231, p = 0.029). Younger age at inclusion (B: 0.23 per 10-years, CI 0.00–0.045, p = 0.047) and low level of education (below ten years) (mean difference: −0.346, CI −0.616 to −0.076, p = 0.012) predicted declining neurocognition.

Our findings support the notion of different schizophrenia subtypes with varying trajectories. Neurocognitive impairment at the 20-year follow-up was associated with other poor outcomes, highlighting the importance of treatments aimed at improving neurocognition in patients with schizophrenia spectrum disorders.

The optimal duration of antipsychotic treatment following remission of first-episode psychosis (FEP) is uncertain, considering potential adverse effects and individual variability in relapse rates. This study aimed to investigate the effect of antipsychotic discontinuation compared to continuation on recovery in remitted FEP patients.

CENTRAL, MEDLINE (Ovid), Embase, and PsycINFO databases were searched on November 2, 2023, with no language restrictions. RCTs evaluating antipsychotic discontinuation in remitted FEP patients were selected. The primary outcome was personal recovery, and secondary outcomes included functional recovery, global functioning, hospital admission, symptom severity, quality of life, side effects, and employment. Risk of bias was assessed using the Cochrane risk-of-bias tool 2, and the certainty of evidence was evaluated with GRADE. Meta-analysis used a random-effect model with an inverse-variance approach.

Among 2185 screened studies, 8 RCTs (560 participants) were included. No RCTs reported personal recovery as an outcome. Two studies measured functional recovery, and discontinuation group patients were more likely to achieve functional recovery (RR 2.19; 95% CIs: 1.13, 4.22; I2 = 0%; n = 128), although evidence certainty was very low. No significant differences were found in hospital admission, symptom severity, quality of life, global functioning, or employment between the discontinuation and continuation groups.

Personal recovery was not reported in any antipsychotic discontinuation trial in remitted FEP. The observed positive effect of discontinuation on functional recovery came from an early terminated trial and an RCT followed by an uncontrolled period. These findings should be interpreted cautiously due to very low certainty of evidence.

The ‘at-risk mental state’ (ARMS) for psychosis has been critiqued for its limited prognostic ability and identification of a limited proportion of those who will develop a first episode of psychosis (FEP). Broadening the search for high-risk groups is key to improving population-level ascertainment of psychosis risk.

To explore risk enrichment in diagnostic, demographic and socio-functional domains among individuals referred to an early intervention in psychosis (EIP) service not meeting ARMS or FEP criteria.

A retrospective file review of 16 years of referrals to a tertiary EIP service in Ireland was undertaken. Diagnostic outcomes from standardised assessments (Structured Clinical Interview for DSM), demographic (age, gender, family history, nationality) and socio-occupational (relationship status, living status, working status) variables were compiled for those not meeting criteria. These were compared with individuals diagnosed with an FEP in the same period.

From 2005 to 2021 inclusive, of 2025 index assessments, 27.6% (n = 558) did not meet either FEP or ARMS criteria, which is notably higher than the 5.4% (n = 110) meeting ARMS criteria. This group had high psychiatric morbidity, with 65.4% meeting criteria for at least one DSM Axis I disorder. Depressive, anxiety and substance use disorders predominated. Their functional markers were poor, and comparable to the FEP cohort.

This group is enriched for psychosis risk factors. They are a larger group than those meeting ARMS criteria, a finding that may reflect EIP service configuration. They may be an important focus for further study in the search for at-risk populations beyond the current ARMS model.

Early intervention programmes (EIPs) in psychosis have gained attention as specialised interventions to improve health-related and societal impacts for people with psychotic disorders. Previous studies have presented evidence in favour of EIPs over the first year of intervention, despite none considering the critical period before psychosis onset (5 years).

To compare the associated costs of the First Episode Psychosis Intervention Program (CRUPEP) and treatment as usual (TAU) in a real-world cohort in a non-specialised psychiatric community setting.

Direct and indirect mental health-related costs were calculated over 1 year and up to 7 years. Healthcare and societal costs were calculated from economic data related to the consumption of all healthcare resources, including emergency department attendances, hospital admissions, psychotropic medication prescriptions and societal costs.

From a healthcare perspective, the intervention (CRUPEP) group initially showed a marginally higher cost per patient than the TAU group (€7621 TAU group v. €11 904 CRUPEP group) over the first year of follow-up. However, this difference was reversed between the groups on considering the entire follow-up, with the TAU group showing considerably higher associated costs per patient (€77 026 TAU v. €25 247 CRUPEP).

The EIP (CRUPEP) showed clinical benefits and minimised the direct and indirect health-related costs of the management of psychosis. Although the CRUPEP intervention initially reported increased costs over 1 year, TAU surpassed the global costs over the entire follow-up.

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.

The coronavirus disease (COVID-19) pandemic produced swift, extensive changes in daily life, including for first-episode psychosis (FEP) clients. This study examined pandemic-related psychosocial impacts to clients while engaged in Coordinated Specialty Care (CSC). We also examined FEP client vaccination rates, as vaccinations can reduce hospitalizations/deaths, and related worries.

Thirty-one clients (45% female; ages 13-39; 26% black, 61% white) from Pennsylvania (PA) CSC outpatient programs completed an online survey evaluating exposure to COVID-19, associated worries, coping, and safety strategies. Descriptive statistics characterized responses and demographic group differences. Additional program evaluation data informed vaccination rates for PA FEP clients.

Participants reported substantial pandemic-related impacts to daily life. Many clients reported improved safety measures to protect themselves/others from COVID-19. Clients largely denied substantial worries about infection for themselves, reporting greater concern for loved ones. Multiple coping strategies were endorsed, which, with few exceptions, did not differ among demographic groups. FEP clients had a low reported rate of vaccination (28.6%) as of September 2021.

Observed prolonged pandemic effects may alter FEP client progress in CSC. Stakeholders should be prepared to adjust FEP treatment accordingly in the event of a similar disaster. Concentrated vaccination efforts may be necessary for this population.

Childhood trauma may impact the course of schizophrenia spectrum disorders (SSD), specifically in relation to the increased severity of depressive or negative symptoms. The type and impact of trauma may differ between sexes. In a large sample of recent-onset patients, we investigated the associations of depressive and negative symptoms with childhood trauma and whether these are sex-specific.

A total of 187 first-episode psychosis patients in remission (Handling Antipsychotic Medication: Long-term Evaluation of Targeted Treatment study) and 115 recent-onset SSD patients (Simvastatin study) were included in this cross-sectional study (men: n = 218; women: n = 84). Total trauma score and trauma subtypes were assessed using the Childhood Trauma Questionnaire Short Form; depressive and negative symptoms were rated using the Positive And Negative Symptoms Scale. Sex-specific regression analyses were performed.

Women reported higher rates of sexual abuse than men (23.5% v. 7.8%). Depressive symptoms were associated with total trauma scores and emotional abuse ratings in men (β: 0.219–0.295; p ≤ 0.001). In women, depressive symptoms were associated with sexual abuse ratings (β: 0.271; p = 0.011). Negative symptoms were associated with total trauma score and emotional neglect ratings in men (β: 0.166–0.232; p ≤ 0.001). Negative symptoms in women were not linked to childhood trauma, potentially due to lack of statistical power.

Depressive symptom severity was associated with different types of trauma in men and women with recent-onset SSD. Specifically, in women, depressive symptom severity was associated with childhood sexual abuse, which was reported three times as often as in men. Our results emphasize the importance of sex-specific analyses in SSD research.

Frequently associated with early psychosis, depressive and manic dimensions may play an important role in its course and outcome. While manic and depressive symptoms can alternate and co-occur, most of the studies in early intervention investigated these symptoms independently. The aim of this study was therefore to explore the co-occurrence of manic and depressive dimensions, their evolution and impact on outcomes.

We prospectively studied first-episode psychosis patients (N = 313) within an early intervention program over 3 years. Based on latent transition analysis, we identified sub-groups of patients with different mood profiles considering both manic and depressive dimensions, and studied their outcomes.

Our results revealed six different mood profiles at program entry and after 1.5 years follow-up (absence of mood disturbance, co-occurrence, mild depressive, severe depressive, manic and hypomanic), and four after 3 years (absence of mood disturbance, co-occurrence, mild depressive and hypomanic). Patients with absence of mood disturbance at discharge had better outcomes. All patients with co-occurring symptoms at program entry remained symptomatic at discharge. Patients with mild depressive symptoms were less likely to return to premorbid functional level at discharge than the other subgroups. Patients displaying a depressive component had poorer quality of physical and psychological health at discharge.

Our results confirm the major role played by mood dimensions in early psychosis, and show that profiles with co-occurring manic and depressive dimensions are at risk of poorer outcome. An accurate assessment and treatment of these dimensions in people with early psychosis is crucial.

Psychotic disorders exhibit a complex aetiology that combines genetic and environmental factors. Among the latter, obstetric complications (OCs) have been widely studied as risk factors, but it is not yet well understood how OCs relate to the heterogeneous presentations of psychotic disorders. We assessed the clinical phenotypes of individuals with a first episode of psychosis (FEP) in relation to the presence of OCs.

Two-hundred seventy-seven patients with an FEP were assessed for OCs using the Lewis–Murray scale, with data stratified into three subscales depending on the timing and the characteristics of the obstetric event, namely: complications of pregnancy, abnormal foetal growth and development and difficulties in delivery. We also considered other two groups: any complications during the pregnancy period and all OCs taken altogether. Patients were clinically evaluated with the Positive and Negative Syndrome Scale for schizophrenia.

Total OCs and difficulties in delivery were related to more severe psychopathology, and this remained significant after co-varying for age, sex, traumatic experiences, antipsychotic dosage and cannabis use.

Our results highlight the relevance of OCs for the clinical presentation of psychosis. Describing the timing of the OCs is essential in understanding the heterogeneity of the clinical presentation.

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.

Resting cerebral blood flow (rCBF) in striatum and thalamus is increased in medicated patients with psychosis, but whether this is caused by treatment or illness pathology is unclear. Specifically, effects of partial dopamine agonism, sex, and clinical correlates on rCBF are sparsely investigated. We therefore assessed rCBF in antipsychotic-naïve psychosis patients before and after aripiprazole monotherapy and related findings to sex and symptom improvement.

We assessed rCBF with the pseudo-Continuous Arterial Spin Labeling (PCASL) sequence in 49 first-episode patients (22.6 ± 5.2 years, 58% females) and 50 healthy controls (HCs) (22.3 ± 4.4 years, 63% females) at baseline and in 29 patients and 49 HCs after six weeks. RCBF in striatum and thalamus was estimated with a region-of-interest (ROI) approach. Psychopathology was assessed with the positive and negative syndrome scale.

Baseline rCBF in striatum and thalamus was not altered in the combined patient group compared with HCs, but female patients had lower striatal rCBF compared with male patients (p = 0.009). Treatment with a partial dopamine agonist increased rCBF significantly in striatum (p = 0.006) in the whole patient group, but not significantly in thalamus. Baseline rCBF in nucleus accumbens was negatively associated with improvement in positive symptoms (p = 0.046), but baseline perfusion in whole striatum and thalamus was not related to treatment outcome.

The findings suggest that striatal perfusion is increased by partial dopamine agonism and decreased in female patients prior to first treatment. This underlines the importance of treatment effects and sex differences when investigating the neurobiology of psychosis.

Sex differences in symptomatology in people with psychosis have been studied extensively in recent decades. Although studies have pointed to such differences, to date there is no review that has performed a systematic search and quantitative synthesis. In this paper, we describe the protocol for a pairwise meta-analysis comparing a range of symptom outcome measures between men and women diagnosed with a psychotic spectrum disorder at different stages of the disorder (PROSPERO registration number CRD42021264942). In August 2021 we conducted systematic searches of PsychInfo, PubMed, Web of Science, Scopus and Dialnet to identify observational studies that report data on symptoms for males and females separately. Two independent reviewers will conduct literature searches, select studies, extract data, assess the risk of bias and assess outcome quality. To assess the effect size of all outcome measures, we will conduct pairwise meta-analysis using random-effects models. The quality of studies will be evaluated using a National Heart, Lung and Blood Institute's quality assessment tool and the confidence in the results will be evaluated using the GRADE tool. Meta-regression and sensitivity analyses will be conducted to assess the robustness of the findings. No ethical problems are foreseen. Results from this study will be published in peer-reviewed journals and presented at relevant conferences.