Psychotic experiences (PEs) and social isolation (SI) seem related during early stages of psychosis, but the temporal dynamics between the two are not clear. Literature so far suggests a self-perpetuating cycle wherein momentary increases in PEs lead to social withdrawal, which, subsequently, triggers PEs at a next point in time, especially when SI is associated with increased distress. The current study investigated the daily-life temporal associations between SI and PEs, as well as the role of SI-related and general affective distress in individuals at clinical high risk (CHR) for psychosis.

We used experience sampling methodology in a sample of 137 CHR participants. We analyzed the association between SI, PEs, and distress using time-lagged linear mixed-effects models.

SI did not predict next-moment fluctuations in PEs, or vice versa. Furthermore, although SI-related distress was not predictive of subsequent PEs, general affective distress during SI was a robust predictor of next-moment PEs.

Our results suggest that SI and PEs are not directly related on a moment-to-moment level, but a negative emotional state when alone does contribute to the risk of PEs. These findings highlight the role of affective wellbeing during early-stage psychosis development.

Clinical implementation of risk calculator models in the clinical high-risk for psychosis (CHR-P) population has been hindered by heterogeneous risk distributions across study cohorts which could be attributed to pre-ascertainment illness progression. To examine this, we tested whether the duration of attenuated psychotic symptom (APS) worsening prior to baseline moderated performance of the North American prodrome longitudinal study 2 (NAPLS2) risk calculator. We also examined whether rates of cortical thinning, another marker of illness progression, bolstered clinical prediction models.

Participants from both the NAPLS2 and NAPLS3 samples were classified as either ‘long’ or ‘short’ symptom duration based on time since APS increase prior to baseline. The NAPLS2 risk calculator model was applied to each of these groups. In a subset of NAPLS3 participants who completed follow-up magnetic resonance imaging scans, change in cortical thickness was combined with the individual risk score to predict conversion to psychosis.

The risk calculator models achieved similar performance across the combined NAPLS2/NAPLS3 sample [area under the curve (AUC) = 0.69], the long duration group (AUC = 0.71), and the short duration group (AUC = 0.71). The shorter duration group was younger and had higher baseline APS than the longer duration group. The addition of cortical thinning improved the prediction of conversion significantly for the short duration group (AUC = 0.84), with a moderate improvement in prediction for the longer duration group (AUC = 0.78).

These results suggest that early illness progression differs among CHR-P patients, is detectable with both clinical and neuroimaging measures, and could play an essential role in the prediction of clinical outcomes.

Emerging meta-analytical evidence indicates that baseline exposure to antipsychotics and to antidepressants in individuals at clinical high-risk for psychosis (CHR-P) have opposite prognostic effects as regards imminent transition to psychosis, with antipsychotics associated with higher risk and antidepressants associated with a lower risk in comparison to not-exposed individuals. Despite their common use, baseline exposure to benzodiazepines (BDZ) in CHR-P has surprisingly received poor attention as a potential risk modulator for transition to psychosis. The current systematic review and meta-analysis were performed to fix such a knowledge gap.

Systematic scrutiny of Medline and Cochrane library, performed up to 31 December 2022, searching for English-language studies on CHR-P reporting numeric data about the sample, the transition outcome at a predefined follow-up time and raw data on BDZ baseline exposure in relation to such outcome.

Of 1893 identified records, five studies were included in the systematic review and meta-analysis. The proportion of participants with exposure to BDZ at baseline ranged from 5.5% (one study) to 46.2%, with an average of 16.8%. At the end of the period of observation, i.e., the follow-up as reported in the study, 28.4% [95% confidence interval (CI) 19.7–39.1%] participants developed psychosis among the BDZ-exposed against 9.3% (7.3 to 11.9%) among the controls. CHR-P participants who were already under BDZ treatment at baseline had more than double chance of transition to psychosis than CHR-P participants who were BDZ-naïve. The risk ratio (RR) was 2.42 (95% CI 1.38–4.23) in the common effects model (z = 3.09; p = 0.002), and 2.40 (1.53 to 3.77) in the random-effects model (z = 5.40; p = 0.006; tau-squared = 0.0). There was no relevant heterogeneity: Cochran's Q = 1.49; df = 4; p = 0.828; I2 = 0.0% (95% CI 0.0–79%). Quality was good in four studies.

Ongoing BDZ exposure at inception in CHR-P is associated with a higher risk of transition to psychosis at follow up. This meta-analytic association, which echoes a similar effect of baseline antipsychotic exposure, plausibly indicates that the clinicians' prescription of pharmacological intervention captures some form of prognostically-relevant information (e.g. an anxiety permeated mental state requiring BDZ prescription) that are not adequately encompassed by current CHR-P categorical criteria.

Negative symptoms such as blunted facial expressivity are characteristic of schizophrenia. However, it is not well-understood if and what abnormalities are present in individuals at clinical high-risk (CHR) for psychosis.

This experimental study employed facial electromyography (left zygomaticus major and left corrugator supercilia) in a sample of CHR individuals (N = 34) and healthy controls (N = 32) to detect alterations in facial expressions in response to emotionally evocative film clips and to determine links with symptoms.

Findings revealed that the CHR group showed facial blunting manifested in reduced zygomatic activity in response to an excitement (but not amusement, fear, or sadness) film clip compared to controls. Reductions in zygomatic activity in the CHR group emerged in response to the emotionally evocative peak period of the excitement film clip. Lower zygomaticus activity during the excitement clip was related to anxiety while lower rates of change in zygomatic activity during the excitement video clip were related to higher psychosis risk conversion scores.

Together, these findings inform vulnerability/disease driving mechanisms and biomarker and treatment development.

The clinical high-risk for psychosis (CHR) is mainly established by the presence of attenuated positive symptoms (APS), but there is evidence of the role of attenuated negative symptoms (ANS) in the development of psychotic spectrum disorders. It is important to establish a link between APS and ANS in patients at CHR in order to improve early detection of psychosis.

Establish the relationship between APS and ANS in depressive patients at CHR.

130 depressive young in-patients at CHR with APS (average age 19.5) and 71 ones with ANS (average age 19.5) were examined. The HDRS scale was used to assess depressive symptoms, the SOPS scale was used to assess APS and ANS, and the SANS scale was used to assess ANS. The results are presented in median values.

No differences were found between two groups in the severity of depressive symptoms on the HDRS scale and CHR symptoms on the SOPS scale (22 vs 23.5 and 45 vs 43 respectively). Statistically valid differences have been established between the groups in the APS severity on the sub-scale of positive symptoms SOPS: 11 and 7 (p 0.001). No differences in the ANS severity on the sub-scale of negative symptoms were detected (17 and 18.5, p=0.207). There were also no differences in the ANS severity on the SANS scale (40 and 47, p=0.163).

It has been established that patients at CHR with APS also have ANS, which may have clinical significance for early detection of psychosis.

No significant relationships.

At present, there is no universally approach to treating patients at clinical high-risk for psychosis (CHR) without comorbid mental disorders. However, if there are revealed depressive symptoms, proper treatment becomes necessary.

Establish pharmacological classes and doses of drugs that have proved effective in treating depressive patients at CHR.

A comparative study of pharmacological classes and doses of drugs was carried out, showing the effectiveness in treatment of 219 depressive patients at CHR and 52 depressive patients without CHR. The treatment effectiveness was carried out on the reduction of depression symptoms on the HDRS scale, and the CHR symptoms on the SOPS scale.

A significant reduction of depression symptoms was achieved in the group of depressive patients with and without CHR on the HDRS scale (67.9% and 76.6% respectively). The reductions of the CHR symptoms were 46.1% and 53.3% respectively. There were differences between the severity of depression symptoms and CHR symptoms before and after the treatment. Both groups used antidepressants followed by the prescription of antipsychotics to increase the effectiveness of the therapy. No difference was found in the doses of antidepressants for the fluoxetine equivalent (46.0 vs 42.6 mg per day, p 0.05) and some differences were found for the average effective doses of antipsychotics for the chlorpromazine equivalent (385.4 vs 230.8 mg per day, p 0.05).

The same pharmacological classes are used for the treatment of young depressive patients with and without CHR, but the former have significantly higher doses of antipsychotics.

No significant relationships.

In addition to the psychosis onset, patients at clinical high-risk (CHR) show a decrease of functioning. This may not be related to the degree and persistence of the attenuated positive symptom (APS). Other clinical factors also predict the level of remission.

Revealing the predictors of the functioning in the 5-year follow-up in patients at CHR.

124 young depressive patients at CHR were examined. Depression symptoms were assessed on the HDRS scale, and the CHR symptoms were assessed on the SOPS scale. The follow-up examination was conducted after 5 years with the determination of functioning on the PSP scale. A correlative analysis of the predictors of the level of remission was conducted.

The functioning level was inversely related to the length of a depressive episode with the CHR symptoms (r=-0,432, p˂0.05), to the negative sub-scale SOPS score (r=0.312, p˂0.05) and to the symptoms of disorganization sub-scale SOPS score (r=0.246, p˂0.05) in the primary assessment. Insufficient reduction of the positive, negative symptoms and symptoms of disorganization on the SOPS during in-patient treatment was also a predictor of the worst outcome at the 5-year follow-up (r=-0,206, p˂0,05; r=-0,309, p˂0,05; r=-0,355, p˂0,05, and r=-0,349, p˂0,05, respectively).

There are some factors, except the severity of APS, that may be considered as the predictors of functioning level in patients at CHR.

No significant relationships.

Early detection of psychosis is a promising area in preventive psychiatry. The use of early intervention can prevent the first episode psychosis and improve outcomes.

Identification of premorbid features of depressive patients at clinical high risk for psychosis (CHR) comparing with depressive patients without CHR in order to improve early recognition of the psychotic process.

219 young depressive in-patients with CHR criteria for SOPS with attenuated positive and attenuated negative symptoms and 52 young depressive in-patients without CHR were examined. Presence of obstetric complications, neurodevelopmental deviance, neurological and psychiatric signs at the premorbid stage, and the level of premorbid functioning on the PAS were examined.

It has been established that depressive patients at CHR and without CHR had some obstetric complications (57.5% and 40.4%, respectively). Neurodevelopmental deviance in the first year of live was in 57.5% patients with CHR. At the age of 3-5 sleep disorders, ADHD and phobias were more common in patients at CHR than without it (58.8% and 32.7%, p=0.014). In pubertal, patients at CHR were more likely to show depression symptoms, obsessions, and aggression - 90.4% versus 76.9% (p=0.029). On the PAS scale, a decrease of the level of premorbid functioning has been observed in two groups of patients with and without CHR from the age of 12: from 12 to 15 years, 0.4 and 0.3 (p=0.004), from 16 to 18 years, 0.47 and 0.37 (p 0.001).

Premorbid functioning were worst in patients with CHR, which indicates the possibility of early clinical detection of psychosis.

No significant relationships.

No significant relationships.

No significant relationships.

The clinical high-risk (CHR) for psychosis paradigm is changing psychiatric practice. However, a widespread confounder, i.e. baseline exposure to antipsychotics (AP) in CHR samples, is systematically overlooked. Such exposure might mitigate the initial clinical presentation, increase the heterogeneity within CHR populations, and confound the evaluation of transition to psychosis at follow-up. This is the first meta-analysis examining the prevalence and the prognostic impact on transition to psychosis of ongoing AP treatment at baseline in CHR cohorts.

Major databases were searched for articles published until 20 April 2020. The variance-stabilizing Freeman-Tukey double arcsine transformation was used to estimate prevalence. The binary outcome of transition to psychosis by group was estimated with risk ratio (RR) and the inverse variance method was used for pooling.

Fourteen studies were eligible for qualitative synthesis, including 1588 CHR individuals. Out of the pooled CHR sample, 370 individuals (i.e. 23.3%) were already exposed to AP at the time of CHR status ascription. Transition toward full-blown psychosis at follow-up intervened in 112 (29%; 95% CI 24–34%) of the AP-exposed CHR as compared to 235 (16%; 14–19%) of the AP-naïve CHR participants. AP-exposed CHR had higher RR of transition to psychosis (RR = 1.47; 95% CI 1.18–1.83; z = 3.48; p = 0.0005), without influence by age, gender ratio, overall sample size, duration of the follow-up, or quality of the studies.

Baseline AP exposure in CHR samples is substantial and is associated with a higher imminent risk of transition to psychosis. Therefore, such exposure should be regarded as a non-negligible red flag for clinical risk management.

Impairments in self-recognition (i.e. recognition of own thoughts and actions) have been repeatedly shown in individuals with schizophrenia. According to classical clinical characterizations, schizophrenia is included in a continuum encompassing a large range of genetic statuses, psychotic states and symptoms. The current meta-analysis aims to determine whether self-recognition is affected by individuals within the psychosis continuum.

Three populations were considered: people with an at-risk mental state for psychosis (ARMS), hallucination-prone individuals and unaffected relatives of patients with schizophrenia. Eleven studies contrasted self-recognition between these three populations (n = 386) and healthy controls (n = 315) and four studies used correlational analysis to estimate comparable effects (n = 629). Eligible studies used experimental paradigms including source-monitoring and self-monitoring.

We observed significantly reduced self-recognition accuracy in these populations [g = −0.44 (−0.71 to −0.17), p = 0.002] compared to controls. No influence of the type of population, experimental paradigm or study design was observed.

The present analysis argues for self-recognition deficits in populations with no full-blown psychotic symptoms represented across the continuum of psychosis.

Several sex differences in schizophrenia have been reported including differences in cognitive functioning. Studies with schizophrenia patients and healthy controls (HC) indicate that the sex advantage for women in verbal domains is also present in schizophrenia patients. However, findings have been inconsistent. No study focused on sex-related cognitive performance differences in at-risk mental state for psychosis (ARMS) individuals yet. Thus, the aim of the present study was to investigate sex differences in cognitive functioning in ARMS, first episode psychosis (FEP) and HC subjects. We expected a better verbal learning and memory performance of women in all groups.

The neuropsychological data analysed in this study were collected within the prospective Früherkennung von Psychosen (FePsy) study. In total, 118 ARMS, 88 FEP individuals and 86 HC completed a cognitive test battery covering the domains of executive functions, attention, working memory, verbal learning and memory, IQ and speed of processing.

Women performed better in verbal learning and memory regardless of diagnostic group. By contrast, men as compared to women showed a shorter reaction time during the working memory task across all groups.

The results provide evidence that women generally perform better in verbal learning and memory, independent of diagnostic group (ARMS, FEP, HC). The finding of a shorter reaction time for men in the working memory task could indicate that men have a superior working memory performance since they responded faster during the target trials, while maintaining a comparable overall working memory performance level.

Sex differences in cognitive functioning have long been recognized in schizophrenia patients and healthy controls (HC). However, few studies have focused on patients with an at-risk mental state (ARMS) for psychosis. Thus, the aim of the present study was to investigate sex differences in neurocognitive performance in ARMS patients compared with HC.

The data analyzed in this study were collected within the multicenter European Gene–Environment Interactions study (11 centers). A total of 343 ARMS patients (158 women) and 67 HC subjects (33 women) were included. All participants completed a comprehensive neurocognitive battery. Linear mixed effects models were used to explore whether sex differences in cognitive functioning were present in the total group (main effect of sex) and whether sex differences were different for HC and ARMS (interaction between sex and group).

Women performed better in social cognition, speed of processing, and verbal learning than men regardless of whether they were ARMS or HC. However, only differences in speed of processing and verbal learning remained significant after correction for multiple testing. Additionally, ARMS patients displayed alterations in attention, current IQ, speed of processing, verbal learning, and working memory compared with HC.

Findings indicate that sex differences in cognitive functioning in ARMS are similar to those seen between healthy men and women. Thus, it appears that sex differences in cognitive performance may not be specific for ARMS, a finding resembling that in patients with schizophrenic psychoses.

Consistent with pathophysiological models of psychosis, temporal disturbances in schizophrenia spectrum populations may reflect abnormal cortical (e.g. prefrontal cortex) and subcortical (e.g. striatum) cerebellar connectivity. However, few studies have examined associations between cerebellar connectivity and timing dysfunction in psychosis populations, and none have been conducted in youth at clinical high-risk (CHR) for psychosis. Thus, it is currently unknown if impairments in temporal processes are present in CHR youth or how they may be associated with cerebellar connectivity and worsening of symptoms.

A total of 108 (56 CHR/52 controls) youth were administered an auditory temporal bisection task along with a resting state imaging scan to examine cerebellar resting state connectivity. Positive and negative symptoms at baseline and 12 months later were also quantified.

Controlling for alcohol and cannabis use, CHR youth exhibited poorer temporal accuracy compared to controls, and temporal accuracy deficits were associated with abnormal connectivity between the bilateral anterior cerebellum and a right caudate/nucleus accumbens striatal cluster. Poor temporal accuracy accounted for 11% of the variance in worsening of negative symptoms over 12 months.

Behavioral findings suggest CHR youth perceive durations of auditory tones as shortened compared to objective time, which may indicate a slower internal clock. Poorer temporal accuracy in CHR youth was associated with abnormalities in brain regions involved in an important cerebellar network implicated in prominent pathophysiological models of psychosis. Lastly, temporal accuracy was associated with worsening of negative symptoms across 12 months, suggesting temporal dysfunction may be sensitive to illness progression.

Evidence has been accumulating regarding alterations in components of the endocannabinoid system in patients with psychosis. Of all the putative risk factors associated with psychosis, being at clinical high-risk for psychosis (CHR) has the strongest association with the onset of psychosis, and exposure to childhood trauma has been linked to an increased risk of development of psychotic disorder. We aimed to investigate whether being at-risk for psychosis and exposure to childhood trauma were associated with altered endocannabinoid levels.

We compared 33 CHR participants with 58 healthy controls (HC) and collected information about previous exposure to childhood trauma as well as plasma samples to analyse endocannabinoid levels.

Individuals with both CHR and experience of childhood trauma had higher N-palmitoylethanolamine (p < 0.001) and anandamide (p < 0.001) levels in peripheral blood compared to HC and those with no childhood trauma. There was also a significant correlation between N-palmitoylethanolamine levels and symptoms as well as childhood trauma.

Our results suggest an association between CHR and/or childhood maltreatment and elevated endocannabinoid levels in peripheral blood, with a greater alteration in those with both CHR status and history of childhood maltreatment compared to those with either of those risks alone. Furthermore, endocannabinoid levels increased linearly with the number of risk factors and elevated endocannabinoid levels correlated with the severity of CHR symptoms and extent of childhood maltreatment. Further studies in larger cohorts, employing longitudinal designs are needed to confirm these findings and delineate the precise role of endocannabinoid alterations in the pathophysiology of psychosis.

The current study examined the pattern of neurocognitive impairments in a community-recruited sample of clinical high-risk (CHR) participants and established relationships with psychosocial functioning.

CHR-participants (n = 108), participants who did not fulfil CHR-criteria (CHR-negatives) (n = 42) as well as a group of healthy controls (HCs) (n = 55) were recruited. CHR-status was assessed using the Comprehensive Assessment of At-Risk Mental States (CAARMS) and the Schizophrenia Proneness Instrument, Adult Version (SPI-A). The Brief Assessment of Cognition in Schizophrenia Battery (BACS) as well as tests for emotion recognition, working memory and attention were administered. In addition, role and social functioning as well as premorbid adjustment were assessed.

CHR-participants were significantly impaired on the Symbol-Coding and Token-Motor task and showed a reduction in total BACS-scores. Moreover, CHR-participants were characterised by prolonged response times (RTs) in emotion recognition as well as by reductions in both social and role functioning, GAF and premorbid adjustments compared with HCs. Neurocognitive impairments in emotion recognition accuracy, emotion recognition RT, processing speed and motor speed were associated with several aspects of functioning explaining between 4% and 12% of the variance.

The current data obtained from a community sample of CHR-participants highlight the importance of dysfunctions in motor and processing speed and emotion recognition RT. Moreover, these deficits were found to be related to global, social and role functioning, suggesting that neurocognitive impairments are an important aspect of sub-threshold psychotic experiences and a possible target for therapeutic interventions.

During vocalization, efference copy/corollary discharge mechanisms suppress the auditory cortical response to self-generated sounds. Previously, we found attenuated vocalization-related auditory cortical suppression in psychosis and a similar trend in the psychosis risk syndrome. Here, we report data from the final sample of early illness schizophrenia patients (ESZ), individuals at clinical high risk for psychosis (CHR), and healthy controls (HC).

Event-related potentials (ERP) were recorded from ESZ (n = 84), CHR (n = 71), and HC (n = 103) participants during a vocalization paradigm. The N1 ERP component was elicited during production (Talk) and playback (Listen) of vocalization. Age effects on N1 suppression (Talk–Listen), Talk N1, and Listen N1 were compared across groups. N1 measures were adjusted for normal aging before testing for group differences.

Both ESZ and CHR groups showed reduced Talk–Listen N1 suppression relative to HC, but did not differ from each other. Listen N1 was reduced in ESZ, but not in CHR, relative to HC. Deficient Talk–Listen N1 suppression was associated with greater unusual thought content in CHR individuals. N1 suppression increased with age in HC (12–36 years), and while CHR individuals showed a similar age-related increase, no such relationship was evident in ESZ.

Putative efference copy/corollary discharge-mediated auditory cortical suppression during vocalization is deficient in ESZ and precedes psychosis onset, particularly in CHR individuals with greater unusual thought content. Furthermore, this suppression increases from adolescence through early adulthood, likely reflecting the effects of normal brain maturation. This maturation effect is disrupted in ESZ, presumably due to countervailing illness effects.