The early phases of severe mental disorders are often diagnostically challenging, with frequent diagnostic shifts over time. Few studies have combined detailed baseline diagnostic assessment with long-term follow-up to examine both diagnostic and social development.

We conducted a 20-year register-based follow-up of 150 patients with first-time psychiatric hospitalizations. At baseline, all participants underwent a comprehensive diagnostic assessment. Follow-up data were obtained through linkage to national registers, providing information on psychiatric diagnoses, education, family formation, crime, mortality, and suicide. Cumulative incidence functions accounting for competing risks were calculated stratified on baseline diagnoses.

Only seven participants (4.6%) had no further contact with hospital-based psychiatry during the 20-year follow-up. During the follow-up period, 37.9% received a diagnosis of schizophrenia, 35% schizotypy, 14.4% depression, 24.6% personality disorder, 11% bipolar disorder, and 6.1% substance use disorder. Participants with a baseline diagnosis of schizophrenia, schizotypy, or depression had a significantly higher probability of receiving the same diagnosis during follow-up (schizophrenia 81.6%, schizotypy 69.4%, and depression 53.3%), whereas this was not the case for participants with a baseline diagnosis of personality disorder. Mortality was elevated (5.9%), with suicide accounting for one-third of all deaths, ten times the national average.

A first psychiatric hospitalization in early adulthood marked the beginning of a longer clinical trajectory: 95% of participants re-entered hospital-based care or had prolonged initial hospitalization. The findings emphasize the importance of diagnostic assessment and sustained care to improve prognosis and reduce social impairment and premature death.

Incidence of first-episode psychosis (FEP) varies substantially across geographic regions. Phenotypes of subclinical psychosis (SP), such as psychotic-like experiences (PLEs) and schizotypy, present several similarities with psychosis. We aimed to examine whether SP measures varied across different sites and whether this variation was comparable with FEP incidence within the same areas. We further examined contribution of environmental and genetic factors to SP.

We used data from 1497 controls recruited in 16 different sites across 6 countries. Factor scores for several psychopathological dimensions of schizotypy and PLEs were obtained using multidimensional item response theory models. Variation of these scores was assessed using multi-level regression analysis to estimate individual and between-sites variance adjusting for age, sex, education, migrant, employment and relational status, childhood adversity, and cannabis use. In the final model we added local FEP incidence as a second-level variable. Association with genetic liability was examined separately.

Schizotypy showed a large between-sites variation with up to 15% of variance attributable to site-level characteristics. Adding local FEP incidence to the model considerably reduced the between-sites unexplained schizotypy variance. PLEs did not show as much variation. Overall, SP was associated with younger age, migrant, unmarried, unemployed and less educated individuals, cannabis use, and childhood adversity. Both phenotypes were associated with genetic liability to schizophrenia.

Schizotypy showed substantial between-sites variation, being more represented in areas where FEP incidence is higher. This supports the hypothesis that shared contextual factors shape the between-sites variation of psychosis across the spectrum.

Psychotic disorders and schizotypal traits aggregate in the relatives of probands with schizophrenia. It is currently unclear how variability in symptom dimensions in schizophrenia probands and their relatives is associated with polygenic liability to psychiatric disorders.

To investigate whether polygenic risk scores (PRSs) can predict symptom dimensions in members of multiplex families with schizophrenia.

The largest genome-wide data-sets for schizophrenia, bipolar disorder and major depressive disorder were used to construct PRSs in 861 participants from the Irish Study of High-Density Multiplex Schizophrenia Families. Symptom dimensions were derived using the Operational Criteria Checklist for Psychotic Disorders in participants with a history of a psychotic episode, and the Structured Interview for Schizotypy in participants without a history of a psychotic episode. Mixed-effects linear regression models were used to assess the relationship between PRS and symptom dimensions across the psychosis spectrum.

Schizophrenia PRS is significantly associated with the negative/disorganised symptom dimension in participants with a history of a psychotic episode (P = 2.31 × 10−4) and negative dimension in participants without a history of a psychotic episode (P = 1.42 × 10−3). Bipolar disorder PRS is significantly associated with the manic symptom dimension in participants with a history of a psychotic episode (P = 3.70 × 10−4). No association with major depressive disorder PRS was observed.

Polygenic liability to schizophrenia is associated with higher negative/disorganised symptoms in participants with a history of a psychotic episode and negative symptoms in participants without a history of a psychotic episode in multiplex families with schizophrenia. These results provide genetic evidence in support of the spectrum model of schizophrenia, and support the view that negative and disorganised symptoms may have greater genetic basis than positive symptoms, making them better indices of familial liability to schizophrenia.

Schizotypy is associated with increased vulnerability to schizophrenia spectrum disorders. Therefore, investigation of its brain correlates seems prominent for better understanding of schizophrenia-spectrum continuum as well as for development of biological treatments for schizotypal personality disorder. Functional alterations of prefrontal cortex (PFC) and their associations with clinical symptoms are well-known to exist in schizophrenia. However, their relevance to schizotypy remains unclear.

The aim of the study was to check for associations between schizotypal traits in a non-clinical sample and whole-brain functional connectivity (FC) of lateral as well as medial PFC (lPFC and mPFC, respectively).

Eighty-two healthy individuals (52 females, mean age 24.8±5.48) filled out the Schizotypal Personality Questionnaire (SPQ-74) and underwent resting-state fMRI (3T). Seeds in lPFC and mPFC were taken from frontoparietal and default mode networks (atlas by Yeo et al., 2011). We analyzed correlations between four schizotypal factors (cognitive/perceptual, paranoid, negative, and disorganization; Stefanis et al., 2004) and whole-brain FC of the seeds (statistical threshold: p<.001 voxelwise; p[FDR]<.05 clusterwise).

Cognitive/perceptual factor (‘Odd beliefs/magical thinking’ and ‘Unusual perceptual experiences’ SPQ-74 subscales) is negatively correlated to FC of bilateral mPFC with a cluster in the right cerebellum (Crus 1, 2).

Prefrontal-cerebellar dysconnectivity may be one of the neurobiological factors underlying positive-symptoms-like schizotypal traits in non-clinical subjects. To some extent, it coincides with the data on associations between functional features of these brain structures and positive symptoms in schizophrenia (Pinheiro et al., 2021; Goghari et al., 2010).

The study was supported by RFBR Grant 20-013-00748.

Insomnia and Nightmare disorder are the two most common comorbid sleep disturbances in psychotic conditions. However, insomnia and psychotic symptoms are umbrella terms that hide the heterogeneity of these concepts. Several studies have found that worsening sleep quality is associated with the strengthening of psychotic symptoms. Until now, there was less interest in the relationship between the specific insomnia symptoms (trouble with falling asleep, fragmented sleep, early awakenings, daytime consequences) and the specific dimensions of schizotypy (disorganization, unusual perceptual experiences, anhedonia, and impulsive nonconformity).

The study aimed to depict the network structure of insomnia, dreaming features (dream recall/bad dream/nightmare frequency), and schizotypy dimensions.

Exploratory network analysis was conducted on cross-sectional data of the general population (N=1419, 77 % female). We modeled the interrelations between insomnia symptoms (Athens Insomnia Scale), dreaming features (the frequency of dream recall/bad dreams/nightmares), and the dimensions of schizotypy (OLIFE-S).

show a highly connected network with strong stability. The nodes of schizotypy, insomnia, and dream feature perfectly correspond to their own clusters, but the nodes were also densely connected between the three clusters. Disorganization, frequent awakenings, and nightmares are the most central nodes of the clusters. The node of frequent nightmares seems to be the bridge symptom in this network which connects unusual experiences dimension and frequent awakenings.

These results suggest that specific dimensions of schizotypy and specific sleep complaints are differently connected. However further research is needed to investigate the finer details of these heterogenic phenomena.

No significant relationships.

Tendency to experience inaccurate beliefs alongside perceptual anomalies constitutes positive schizotypal traits in the general population and shows continuity with the positive symptoms of schizophrenia. It has been hypothesized that the positive symptomatology of schizophrenia, and by extension, positive schizotypy, are associated with specific alterations in memory functions. Imbalance between memory generalization and episodic memory specificity has been proposed on several counts; however, the direction of the imbalance is currently unclear.

We aimed to contrast two competing hypotheses regarding the association between positive schizotypy, and memory alterations in a general population sample (N=71) enriched for positive schizotypy from a larger pool of individuals (N=614).

Positive schizotypy was measured with the short-version of the O-LIFE questionnaire, and memory specificity and generalization was captured by the well-established Mnemonic Similarity Task.

Distortions in the behavioural memory performance indices were found to correlate with positive schizotypy: individuals prone to unusual experiences demonstrated increased discrimination and reduced generalization (explaining 10% and 17% of variance, respectively). Associations were robust when controlled for the disorganized, negative and impulsive-asocial dimensions of schizotypy and associated psychopathology.

Our findings show that people who are prone to irrational beliefs and unusual experiences also show measurable alterations in memory and likely have difficulty grasping the global picture and rather be overpowered by fragments of information.

No significant relationships.

Patients with schizophrenia and individuals with schizotypy, a subclinical group at risk for schizophrenia, have been found to have impairments in cognitive control. The Dual Mechanisms of Cognitive Control (DMC) framework hypothesises that cognitive control can be divided into proactive and reactive control. However, it is unclear whether individuals with schizotypy have differential behavioural impairments and neural correlates underlying these two types of cognitive control.

Twenty-five individuals with schizotypy and 26 matched healthy controls (HCs) completed both reactive and proactive control tasks with electroencephalographic data recorded. The proportion of congruent and incongruent trials was manipulated in a classic colour-word Stroop task to induce proactive or reactive control. Proactive control was induced in a context with mostly incongruent (MI) trials and reactive control in a context with mostly congruent (MC) trials. Two event-related potential (ERP) components, medial frontal negativity (MFN, associated with conflict detection) and conflict sustained potential (conflict SP, associated with conflict resolution) were examined.

There was no significant difference between the two groups in terms of behavioural results. In terms of ERP results, in the MC context, HC exhibited significantly larger MFN (360–530 ms) and conflict SP (600–1000 ms) amplitudes than individuals with schizotypy. The two groups did not show any significant difference in MFN or conflict SP in the MI context.

The present findings provide initial evidence for dissociation of neural activation between proactive and reactive cognitive control in individuals with schizotypy. These findings help us understand cognitive control deficits in the schizophrenia spectrum.

Psychosis spectrum disorder has a complex pathoetiology characterised by interacting environmental and genetic vulnerabilities. The present study aims to investigate the role of gene–environment interaction using aggregate scores of genetic (polygenic risk score for schizophrenia (PRS-SCZ)) and environment liability for schizophrenia (exposome score for schizophrenia (ES-SCZ)) across the psychosis continuum.

The sample consisted of 1699 patients, 1753 unaffected siblings, and 1542 healthy comparison participants. The Structured Interview for Schizotypy-Revised (SIS-R) was administered to analyse scores of total, positive, and negative schizotypy in siblings and healthy comparison participants. The PRS-SCZ was trained using the Psychiatric Genomics Consortiums results and the ES-SCZ was calculated guided by the approach validated in a previous report in the current data set. Regression models were applied to test the independent and joint effects of PRS-SCZ and ES-SCZ (adjusted for age, sex, and ancestry using 10 principal components).

Both genetic and environmental vulnerability were associated with case-control status. Furthermore, there was evidence for additive interaction between binary modes of PRS-SCZ and ES-SCZ (above 75% of the control distribution) increasing the odds for schizophrenia spectrum diagnosis (relative excess risk due to interaction = 6.79, [95% confidential interval (CI) 3.32, 10.26], p < 0.001). Sensitivity analyses using continuous PRS-SCZ and ES-SCZ confirmed gene–environment interaction (relative excess risk due to interaction = 1.80 [95% CI 1.01, 3.32], p = 0.004). In siblings and healthy comparison participants, PRS-SCZ and ES-SCZ were associated with all SIS-R dimensions and evidence was found for an interaction between PRS-SCZ and ES-SCZ on the total (B = 0.006 [95% CI 0.003, 0.009], p < 0.001), positive (B = 0.006 [95% CI, 0.002, 0.009], p = 0.002), and negative (B = 0.006, [95% CI 0.004, 0.009], p < 0.001) schizotypy dimensions.

The interplay between exposome load and schizophrenia genetic liability contributing to psychosis across the spectrum of expression provide further empirical support to the notion of aetiological continuity underlying an extended psychosis phenotype.

Schizotypy is a putative risk phenotype for psychosis liability, but the overlap of its genetic architecture with schizophrenia is poorly understood.

We tested the hypothesis that dimensions of schizotypy (assessed with the SPQ-B) are associated with a polygenic risk score (PRS) for schizophrenia in a sample of 623 psychiatrically healthy, non-clinical subjects from the FOR2107 multi-centre study and a second sample of 1133 blood donors.

We did not find correlations of schizophrenia PRS with either overall SPQ or specific dimension scores, nor with adjusted schizotypy scores derived from the SPQ (addressing inter-scale variance). Also, PRS for affective disorders (bipolar disorder and major depression) were not significantly associated with schizotypy.

This important negative finding demonstrates that despite the hypothesised continuum of schizotypy and schizophrenia, schizotypy might share less genetic risk with schizophrenia than previously assumed (and possibly less compared to psychotic-like experiences).

Schizotypy refers to schizophrenia-like traits below the clinical threshold in the general population. The pathological development of schizophrenia has been postulated to evolve from the initial coexistence of ‘brain disconnection’ and ‘brain connectivity compensation’ to ‘brain connectivity decompensation’.

In this study, we examined the brain connectivity changes associated with schizotypy by combining brain white matter structural connectivity, static and dynamic functional connectivity analysis of diffusion tensor imaging data and resting-state functional magnetic resonance imaging data. A total of 87 participants with a high level of schizotypal traits and 122 control participants completed the experiment. Group differences in whole-brain white matter structural connectivity probability, static mean functional connectivity strength, dynamic functional connectivity variability and stability among 264 brain sub-regions of interests were investigated.

We found that individuals with high schizotypy exhibited increased structural connectivity probability within the task control network and within the default mode network; increased variability and decreased stability of functional connectivity within the default mode network and between the auditory network and the subcortical network; and decreased static mean functional connectivity strength mainly associated with the sensorimotor network, the default mode network and the task control network.

These findings highlight the specific changes in brain connectivity associated with schizotypy and indicate that both decompensatory and compensatory changes in structural connectivity within the default mode network and the task control network in the context of whole-brain functional disconnection may be an important neurobiological correlate in individuals with high schizotypy.

Subclinical psychotic-like experiences (PLE), resembling key symptoms of psychotic disorders, are common throughout the general population and possibly associated with psychosis risk. There is evidence that such symptoms are also associated with structural brain changes.

In 672 healthy individuals, we assessed PLE and associated distress with the symptom-checklist-90R (SCL-90R) scales ‘schizotypal signs’ (STS) and ‘schizophrenia nuclear symptoms’ (SNS) and analysed associations with voxel- and surfaced-based brain structural parameters derived from structural magnetic resonance imaging at 3 T with CAT12.

For SNS, we found a positive correlation with the volume in the left superior parietal lobule and the precuneus, and a negative correlation with the volume in the right inferior temporal gyrus [p < 0.05 cluster-level Family Wise Error (FWE-corrected]. For STS, we found a negative correlation with the volume of the left and right precentral gyrus (p < 0.05 cluster-level FWE-corrected). Surface-based analyses did not detect any significant clusters with the chosen statistical threshold of p < 0.05. However, in exploratory analyses (p < 0.001, uncorrected), we found a positive correlation of SNS with gyrification in the left insula and rostral middle frontal gyrus and of STS with the left precuneus and insula, as well as a negative correlation of STS with gyrification in the left temporal pole.

Our results show that brain structures in areas implicated in schizophrenia are also related to PLE and its associated distress in healthy individuals. This pattern supports a dimensional model of the neural correlates of symptoms of the psychotic spectrum.

Previous findings indicated that schizophrenia patients might have a different personality structure from the general population on several dimensions of temperament and character. Some authors proposed that HA might be a marker of underlying genetic vulnerability to schizophrenia. Studies on high-risk subjects and first degree relatives of patients is essential to test the value of a measure as a marker of genetic vulnerability to a disease. Few studies tested the biopsychosocial model of personality on unaffected relatives of schizophrenia.

We compared the Temperament and Character (TCI) profiles of 94 first degree relatives of schizophrenia and 75 controls. We also investigated the relationship between schizotypy and TCI dimensions in the study sample.

The harm avoidance scores of the relatives of schizoprenia patients with schizotypal features were significantly higher. Self transcendence scores were also significantly higher among relatives with schizotypal features. In contrast, the relatives of the patients with schizophrenia who did not have schizotypal features had higher SD and C scores than the control group.

This finding is consistent with the previous findings which suggested harm avoidance as a vulnerability indicator of schizophrenia. Some character features like self transcendence might be also associated with schizotypal features.

Except in broad outline, little is known about the most likely symptomatic trajectories in prodromal schizophrenia. The aim of this study is to delineate these pathways.

Taking into account existing clinical knowledge, the causal relationships between the 12 prodrome scales of the Schizotypic Syndrome Questionnaire (SSQ) were examined in a general-population sample by applying the mathematical theory of directed graphs. Use was made of two discovery algorithms implemented in the Tetrad-4 program, as well as of the graphical DAGitty program to test whether a particular model holds.

A promising model was selected that may describe the causal pathways in schizophrenic prodromal unfolding. Testing this model by means of DAGitty, it was shown that the minimal testable implications, listed as conditional independences, and the direct and total effects in the model, identified after correction for bias, were as hypothesized. For practical reasons, a simpler version of the resulting SSQ model, containing only its principal pathways, was provided.

Although resembling an earlier model that was based on a series of LISREL analyses, the present model was believed to provide a more dependable description of schizophrenic prodromal unfolding, as it relies on methods that are less subject to the limitations involved in SEM.