The negative symptoms of psychosis are heterogeneous, which complicates efforts to understand their pathophysiology and develop effective treatments. Factor analytic studies of the Positive and Negative Syndrome Scale (PANSS) have reported two factorial negative symptom models, expressive deficit and social amotivation, albeit with different compositions. Although models derived from other assessment scales have been directly compared, no study has previously applied this approach to PANSS.

Our objectives were to (a) to establish which negative PANSS-derived factorial model provided the best fit to our data, (b) test its stability and (c) determine its clinical and demographic correlates.

A cohort of medication naive or minimally treated patients with first-episode schizophrenia (n = 446) were assessed using the PANSS scale before and 4 weeks after amisulpride treatment. Confirmatory factor analysis was performed to test five PANSS models. Hierarchical multiple regression was conducted to examine the associations between identified dimensions and clinical and demographic variables.

A nine-item PANSS model comprising social amotivation and expressive deficit dimensions outperformed the other models: comparative fit index = 0.98, goodness of fit index = 0.97, Tucker–Lewis index = 0.97, root mean square error of approximation = 0.06 (CI 90%: 0.04–0.08), Bayesian information criterion = 191.9, Akaike information criterion = 101.7. At baseline, the social amotivation dimension was associated with more severe depression whereas the expressive deficit dimension was associated with younger age. Both dimensions at baseline were associated with poor functioning, but expressive deficit to a lesser extent.

A nine-item PANSS model incorporating social amotivation and expressive deficit dimensions appeared to best reflect the underlying structure of negative symptoms in our sample.

Preclinical evidence suggests that diazepam enhances hippocampal γ-aminobutyric acid (GABA) signalling and normalises a psychosis-relevant cortico-limbic-striatal circuit. Hippocampal network dysconnectivity, particularly from the CA1 subfield, is evident in people at clinical high-risk for psychosis (CHR-P), representing a potential treatment target. This study aimed to forward-translate this preclinical evidence.

In this randomised, double-blind, placebo-controlled study, 18 CHR-P individuals underwent resting-state functional magnetic resonance imaging twice, once following a 5 mg dose of diazepam and once following a placebo. They were compared to 20 healthy controls (HC) who did not receive diazepam/placebo. Functional connectivity (FC) between the hippocampal CA1 subfield and the nucleus accumbens (NAc), amygdala, and ventromedial prefrontal cortex (vmPFC) was calculated. Mixed-effects models investigated the effect of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on CA1-to-region FC.

In the placebo condition, CHR-P individuals showed significantly lower CA1-vmPFC (Z = 3.17, PFWE = 0.002) and CA1-NAc (Z = 2.94, PFWE = 0.005) FC compared to HC. In the diazepam condition, CA1-vmPFC FC was significantly increased (Z = 4.13, PFWE = 0.008) compared to placebo in CHR-P individuals, and both CA1-vmPFC and CA1-NAc FC were normalised to HC levels. In contrast, compared to HC, CA1-amygdala FC was significantly lower contralaterally and higher ipsilaterally in CHR-P individuals in both the placebo and diazepam conditions (lower: placebo Z = 3.46, PFWE = 0.002, diazepam Z = 3.33, PFWE = 0.003; higher: placebo Z = 4.48, PFWE < 0.001, diazepam Z = 4.22, PFWE < 0.001).

This study demonstrates that diazepam can partially restore hippocampal CA1 dysconnectivity in CHR-P individuals, suggesting that modulation of GABAergic function might be useful in the treatment of this clinical group.

The macro-social and environmental conditions in which people live, such as the level of a country’s development or inequality, are associated with brain-related disorders. However, the relationship between these systemic environmental factors and the brain remains unclear. We aimed to determine the association between the level of development and inequality of a country and the brain structure of healthy adults.

We conducted a cross-sectional study pooling brain imaging (T1-based) data from 145 magnetic resonance imaging (MRI) studies in 7,962 healthy adults (4,110 women) in 29 different countries. We used a meta-regression approach to relate the brain structure to the country’s level of development and inequality.

Higher human development was consistently associated with larger hippocampi and more expanded global cortical surface area, particularly in frontal areas. Increased inequality was most consistently associated with smaller hippocampal volume and thinner cortical thickness across the brain.

Our results suggest that the macro-economic conditions of a country are reflected in its inhabitants’ brains and may explain the different incidence of brain disorders across the world. The observed variability of brain structure in health across countries should be considered when developing tools in the field of personalized or precision medicine that are intended to be used across the world.

Recent stressful life events (SLE) are a risk factor for psychosis, but limited research has explored how SLEs affect individuals at clinical high risk (CHR) for psychosis. The current study investigated the longitudinal effects of SLEs on functioning and symptom severity in CHR individuals, where we hypothesized CHR would report more SLEs than healthy controls (HC), and SLEs would be associated with poorer outcomes.

The study used longitudinal data from the EU-GEI High Risk study. Data from 331 CHR participants were analyzed to examine the effects of SLEs on changes in functioning, positive and negative symptoms over a 2-year follow-up. We compared the prevalence of SLEs between CHR and HCs, and between CHR who did (CHR-T) and did not (CHR-NT) transition to psychosis.

CHR reported 1.44 more SLEs than HC (p < 0.001), but there was no difference in SLEs between CHR-T and CHR-NT at baseline. Recent SLEs were associated with poorer functioning and more severe positive and negative symptoms in CHR individuals (all p < 0.01) but did not reveal a significant interaction with time.

CHR individuals who had experienced recent SLEs exhibited poorer functioning and more severe symptoms. However, as the interaction between SLEs and time was not significant, this suggests SLEs did not contribute to a worsening of symptoms and functioning over the study period. SLEs could be a key risk factor to becoming CHR for psychosis, however further work is required to inform when early intervention strategies mitigating against the effects of stress are most effective.

Abrupt cessation of heavy cannabis use can cause a withdrawal syndrome characterised by irritability, anxiety, insomnia, reduced appetite and restlessness. Recent reports have also described people in whom cannabis withdrawal immediately preceded the acute onset of psychosis.

To identify cases of psychosis associated with cannabis withdrawal.

We completed a systematic review of the literature, which comprised case reports, case series and other studies. We also searched a large electronic database of psychiatric healthcare records.

The systematic review identified 44 individuals from 21 studies in whom cannabis withdrawal preceded the development of acute psychosis. In the health record study, we identified another 68 people, of whom 47 involved a first episode of psychosis and 21 represented further episodes of an existing psychotic disorder. Almost all people were daily cannabis users who had stopped using cannabis abruptly. Individuals who continued to use cannabis after the acute psychotic episode had a much higher risk of subsequent relapse than those who abstained (odds ratio 13.9 [95% CI: 4.1 to 56.9]; χ2 = 20.1, P < 0.00001).

Abrupt cannabis withdrawal may act as a trigger for the first episode of psychosis and a relapse of an existing psychosis. Acute psychotic symptoms can emerge after the cessation, as well as following the use, of cannabis.

Sexually transmitted infections (STIs), along with sexual health and behaviour, have received little attention in schizophrenia patients.

To systematically review and meta-analytically characterise the prevalence of STIs and sexual risk behaviours among schizophrenia patients.

Web of Science, PubMed, BIOSIS, KCI-Korean Journal Database, MEDLINE, Russian Science Citation Index, SciELO and Cochrane Central Register were systematically searched from inception to 6 July 2023. Studies reporting on the prevalence or odds ratio of any STI or any outcome related to sexual risk behaviours among schizophrenia samples were included. PRISMA/MOOSE-compliant (CRD42023443602) random-effects meta-analyses were used for the selected outcomes. Q-statistics, I2 index, sensitivity analyses and meta-regressions were used. Study quality and publication bias were assessed.

Forty-eight studies (N = 2 459 456) reporting on STI prevalence (including 15 allowing for calculation of an odds ratio) and 33 studies (N = 4255) reporting on sexual risk behaviours were included. Schizophrenia samples showed a high prevalence of STIs and higher risks of HIV (odds ratio = 2.11; 95% CI 1.23–3.63), hepatitis C virus (HCV, odds ratio = 4.54; 95% CI 2.15–961) and hepatitis B virus (HBV; odds ratio = 2.42; 95% CI 1.95–3.01) infections than healthy controls. HIV prevalence was higher in Africa compared with other continents and in in-patient (rather than out-patient) settings. Finally, 37.7% (95% CI 31.5–44.4%) of patients were sexually active; 35.0% (95% CI 6.6–59.3%) reported consistent condom use, and 55.3% (95% CI 25.0–82.4%) maintained unprotected sexual relationships.

Schizophrenia patients have high prevalence of STIs, with several-fold increased risks of HIV, HBV and HCV infection compared with the general population. Sexual health must be considered as an integral component of care.

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.

Hippocampal hyperperfusion has been observed in people at Clinical High Risk for Psychosis (CHR), is associated with adverse longitudinal outcomes and represents a potential treatment target for novel pharmacotherapies. Whether cannabidiol (CBD) has ameliorative effects on hippocampal blood flow (rCBF) in CHR patients remains unknown.

Using a double-blind, parallel-group design, 33 CHR patients were randomized to a single oral 600 mg dose of CBD or placebo; 19 healthy controls did not receive any drug. Hippocampal rCBF was measured using Arterial Spin Labeling. We examined differences relating to CHR status (controls v. placebo), effects of CBD in CHR (placebo v. CBD) and linear between-group relationships, such that placebo > CBD > controls or controls > CBD > placebo, using a combination of hypothesis-driven and exploratory wholebrain analyses.

Placebo-treated patients had significantly higher hippocampal rCBF bilaterally (all pFWE<0.01) compared to healthy controls. There were no suprathreshold effects in the CBD v. placebo contrast. However, we found a significant linear relationship in the right hippocampus (pFWE = 0.035) such that rCBF was highest in the placebo group, lowest in controls and intermediate in the CBD group. Exploratory wholebrain results replicated previous findings of hyperperfusion in the hippocampus, striatum and midbrain in CHR patients, and provided novel evidence of increased rCBF in inferior-temporal and lateral-occipital regions in patients under CBD compared to placebo.

These findings suggest that hippocampal blood flow is elevated in the CHR state and may be partially normalized by a single dose of CBD. CBD therefore merits further investigation as a potential novel treatment for this population.

The antipsychotic aripiprazole is often used in the treatment of first-episode psychosis. Measuring aripiprazole blood levels provides an objective measure of treatment adherence, but this currently involves taking a venous blood sample and sending to a laboratory for analysis.

To detail the development, validation and utility of a new point of care (POC) test for finger-stick capillary blood concentrations of aripiprazole.

Analytical performance (sensitivity, precision, recovery and linearity) of the assay were established using spiked whole blood and control samples of varying aripiprazole concentration. Assay validation was performed over a 14-month period starting in July 2021. Eligible patients were asked to provide a finger-stick capillary sample in addition to their usual venous blood sample. Capillary blood samples were tested by the MyCare™ Insite POC analyser, which provided measurement of aripiprazole concentration in 6 min, and the venous blood sample was tested by the standard laboratory method.

A total of 101 patients agreed to measurements by the two methods. Venous blood aripiprazole concentrations as assessed by the laboratory method ranged from 17 to 909 ng/mL, and from 1 to 791 ng/mL using POC testing. The correlation coefficient between the two methods (r) was 0.96 and there was minimal bias (slope 0.91, intercept 4 ng/ml).

The MyCare Insite POC analyser is sufficiently accurate and reliable for clinical use. The availability of this technology will improve the assessment of adherence to aripiprazole and the optimising of aripiprazole dosing.

To minimise infection during COVID-19, the clozapine haematological monitoring interval was extended from 4-weekly to 12-weekly intervals in South London and Maudsley NHS Foundation Trust.

To investigate the impact of this temporary policy change on clinical and safety outcomes.

All patients who received clozapine treatment with extended (12-weekly) monitoring in a large London National Health Service trust were included in a 1-year mirror-image study. A comparison group was selected with standard monitoring. The proportion of participants with mild to severe neutropenia and the proportion of participants attending the emergency department for clozapine-induced severe neutropenia treatment during the follow-up period were compared. Psychiatric hospital admission rates, clozapine dose and concomitant psychotropic medication in the 1 year before and the 1 year after extended monitoring were compared. All-cause clozapine discontinuation at 1-year follow-up was examined.

Of 569 participants, 459 received clozapine with extended monitoring and 110 controls continued as normal. The total person-years were 458 in the intervention group and 109 in the control group, with a median follow-up time of 1 year in both groups. During follow-up, two participants (0.4%) recorded mild to moderate neutropenia in the intervention group and one (0.9%) in the control group. There was no difference in the incidence of haematological events between the two groups (IRR = 0.48, 95% CI 0.02–28.15, P = 0.29). All neutropenia cases in the intervention group were mild, co-occurring during COVID-19 infection. The median number of admissions per patient during the pre-mirror period remained unchanged (0, IQR = 0) during the post-mirror period. There was one death in the control group, secondary to COVID-19 infection.

There was no evidence that the incidence of severe neutropenia was increased in those receiving extended monitoring.

Adverse childhood experiences (ACE) can affect educational attainments, but little is known about their impact on educational achievements in people at clinical high risk of psychosis (CHR).

In total, 344 CHR individuals and 67 healthy controls (HC) were recruited as part of the European Community’s Seventh Framework Programme-funded multicenter study the European Network of National Schizophrenia Networks Studying Gene–Environment Interactions (EU-GEI). The brief version of the Child Trauma Questionnaire was used to measure ACE, while educational attainments were assessed using a semi-structured interview.

At baseline, compared with HC, the CHR group spent less time in education and had higher rates of ACE, lower rates of employment, and lower estimated intelligence quotient (IQ). Across both groups, the total number of ACE was associated with fewer days in education and lower level of education. Emotional abuse was associated with fewer days in education in HC. Emotional neglect was associated with a lower level of education in CHR, while sexual abuse was associated with a lower level of education in HC. In the CHR group, the total number of ACE, physical abuse, and neglect was significantly associated with unemployment, while emotional neglect was associated with employment.

ACE are strongly associated with developmental outcomes such as educational achievement. Early intervention for psychosis programs should aim at integrating specific interventions to support young CHR people in their educational and vocational recovery. More generally, public health and social interventions focused on the prevention of ACE (or reduce their impact if ACE occur) are recommended.

Clozapine is licensed for treatment-resistant psychosis and remains underutilised. This may berelated to the stringent haematological monitoring requirements that are mandatory in most countries. We aimed to compare guidelines internationally and develop a novel Stringency Index. We hypothesised that the most stringent countries would have increased healthcare costs and reduced prescription rates.

We conducted a literature review and survey of guidelines internationally. Guideline identification involved a literature review and consultation with clinical academics. We focused on the haematological monitoring parameters, frequency and thresholds for discontinuation and rechallenge after suspected clozapine-induced neutropenia. In addition, indicators reflecting monitoring guideline stringency were scored and visualised using a choropleth map. We developed a Stringency Index with an international panel of clozapine experts, through a modified-Delphi-survey. The Stringency Index was compared to health expenditure per-capita and clozapine prescription per 100 000 persons.

One hundred twocountries were included, from Europe (n = 35), Asia (n = 24), Africa (n = 20), South America (n = 11), North America (n = 7) and Oceania and Australia (n = 5). Guidelines differed in frequency of haematological monitoring and discontinuation thresholds. Overall, 5% of included countries had explicit guidelines for clozapine-rechallenge and 40% explicitly prohibited clozapine-rechallenge. Furthermore, 7% of included countries had modified discontinuation thresholds for benign ethnic neutropenia. None of the guidelines specified how long haematological monitoring should continue. The most stringent guidelines were in Europe, and the least stringent were in Africa and South America. There was a positive association (r = 0.43, p < 0.001) between a country's Stringency Index and healthcare expenditure per capita.

Recommendations on how haematological function should be monitored in patients treated with clozapine vary considerably between countries. It would be useful to standardise guidelines on haematological monitoring worldwide.

Cognitive Bias Modification for paranoia (CBM-pa) is a novel, theory-driven psychological intervention targeting the biased interpretation of emotional ambiguity associated with paranoia. Study objectives were (i) test the intervention's feasibility, (ii) provide effect size estimates, (iii) assess dose–response and (iv) select primary outcomes for future trials.

In a double-blind randomised controlled trial, sixty-three outpatients with clinically significant paranoia were randomised to either CBM-pa or an active control (text reading) between April 2016 and September 2017. Patients received one 40 min session per week for 6 weeks. Assessments were given at baseline, after each interim session, post-treatment, and at 1- and 3-months post-treatment.

A total of 122 patients were screened and 63 were randomised. The recruitment rate was 51.2%, with few dropouts (four out of 63) and follow-up rates were 90.5% (1-month) and 93.7% (3-months). Each session took 30–40 min to complete. There was no statistical evidence of harmful effects of the intervention. Preliminary data were consistent with efficacy of CBM-pa over text-reading control: patients randomised to the intervention, compared to control patients, reported reduced interpretation bias (d = −0.48 to −0.76), improved symptoms of paranoia (d = −0.19 to −0.38), and lower depressed and anxious mood (d = −0.03 to −0.29). The intervention effect was evident after the third session.

CBM-pa is feasible for patients with paranoia. A fully powered randomised control trial is warranted.

The coronavirus disease 2019 (COVID-19) pandemic has been a global challenge. High mortality rates have been reported in some risk groups, including patients with pre-existing mental disorders.

We used electronic health records to retrospectively identify people infected due to COVID-19 (between March 2020 and March 2021) in the three territories of the Basque Country. COVID-19 cases were defined as individuals who had tested positive on a reverse transcription-polymerase chain reaction (PCR) test. Univariate and multivariate logistic regression models and multilevel analyses with generalized estimated equations were used to determine factors associated with COVID-19-related mortality and hospital admission.

The COVID-19 mortality rate was increased for patients with psychotic disorders [odds ratio (OR) adjusted: 1.45, 95% confidence interval (CI) (1.09–1.94), p = 0.0114] and patients with substance abuse [OR adjusted: 1.88, 95% CI (1.13–3.14, p < 0.0152)]. The mortality rate was lower for patients with affective disorders [OR adjusted: 0.80, 95% CI (0.61–0.99), p = 0.0407]. Hospital admission rates due to COVID-19 were higher in psychosis [OR adjusted: 2.90, 95% CI (2.36–3.56), p < 0.0001] and anxiety disorder groups [OR adjusted: 1.54, 95% CI (1.37–1.72), p < 0.0001]. Among admitted patients, COVID-19 mortality rate was decreased for those with affective disorders rate [OR adjusted: 0.72, 95% CI (0.55–0.95), p = 0.0194].

COVID-19-related mortality and hospitalizations rates were higher for patients with a pre-existing psychotic disorder.

Negative symptoms are one of the most incapacitating features of Schizophrenia but their pathophysiology remains unclear. They have been linked to alterations in grey matter in several brain regions, but findings have been inconsistent. This may reflect the investigation of relatively small patient samples, and the confounding effects of chronic illness and exposure to antipsychotic medication. We sought to address these issues by investigating concurrently grey matter volumes (GMV) and cortical thickness (CTh) in a large sample of antipsychotic-naïve or minimally treated patients with First-Episode Schizophrenia (FES).

T1-weighted structural MRI brain scans were acquired from 180 antipsychotic-naïve or minimally treated patients recruited as part of the OPTiMiSE study. The sample was stratified into subgroups with (N = 88) or without (N = 92) Prominent Negative Symptoms (PMN), based on PANSS ratings at presentation. Regional GMV and CTh in the two groups were compared using Voxel-Based Morphometry (VBM) and FreeSurfer (FS). Between-group differences were corrected for multiple comparisons via Family-Wise Error (FWE) and Monte Carlo z-field simulation respectively at p < 0.05 (2-tailed).

The presence of PMN symptoms was associated with larger left inferior orbitofrontal volume (p = 0.03) and greater CTh in the left lateral orbitofrontal gyrus (p = 0.007), but reduced CTh in the left superior temporal gyrus (p = 0.009).

The findings highlight the role of orbitofrontal and temporal cortices in the pathogenesis of negative symptoms of Schizophrenia. As they were evident in generally untreated FEP patients, the results are unlikely to be related to effects of previous treatment or illness chronicity.

The clinical outcomes of individuals at clinical high risk of psychosis (CHR-P) who do not transition to psychosis are heterogeneous and inconsistently reported. We aimed to comprehensively evaluate longitudinally a wide range of outcomes in CHR-P individuals not developing psychosis.

“Preferred Reporting Items for Systematic reviews and Meta-Analyses” and “Meta-analysis Of Observational Studies in Epidemiology”-compliant meta-analysis (PROSPERO: CRD42021229212) searching original CHR-P longitudinal studies in PubMed and Web of Science databases up to 01/11/2021. As primary analysis, we evaluated the following outcomes within CHR-P non-transitioning individuals: (a) change in the severity of attenuated psychotic symptoms (Hedge's g); (b) change in the severity of negative psychotic symptoms (Hedge's g); (c) change in the severity of depressive symptoms (Hedge's g); (d) change in the level of functioning (Hedge's g); (e) frequency of remission (at follow-up). As a secondary analysis, we compared these outcomes in those CHR-P individuals who did not transition vs. those who did transition to psychosis at follow-up. We conducted random-effects model meta-analyses, sensitivity analyses, heterogeneity analyses, meta-regressions and publication bias assessment. The risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale (NOS).

Twenty-eight studies were included (2756 CHR-P individuals, mean age = 20.4, 45.5% females). The mean duration of follow-up of the included studies was of 30.7 months. Primary analysis: attenuated psychotic symptoms [Hedges’ g = 1.410, 95% confidence interval (CI) 1.002–1.818]; negative psychotic symptoms (Hedges’ g = 0.683, 95% CI 0.371–0.995); depressive symptoms (Hedges’ g = 0.844, 95% CI 0.371–1.317); and functioning (Hedges’ g = 0.776, 95% CI 0.463–1.089) improved in CHR-P non-transitioning individuals; 48.7% remitted at follow-up (95% CI 39.3–58.2%). Secondary analysis: attenuated psychotic symptoms (Hedges’ g = 0.706, 95% CI 0.091–1.322) and functioning (Hedges’ g = 0.623, 95% CI 0.375–0.871) improved in CHR-P individuals not-transitioning compared to those transitioning to psychosis, but there were no differences in negative or depressive symptoms or frequency of remission (p > 0.05). Older age was associated with higher improvements of attenuated psychotic symptoms (β = 0.225, p = 0.012); publication years were associated with a higher improvement of functioning (β = −0.124, p = 0.0026); a lower proportion of Brief Limited Intermittent Psychotic Symptoms was associated with higher frequencies of remission (β = −0.054, p = 0.0085). There was no metaregression impact for study continent, the psychometric instrument used, the quality of the study or proportion of females. The NOS scores were 4.4 ± 0.9, ranging from 3 to 6, revealing the moderate quality of the included studies.

Clinical outcomes improve in CHR-P individuals not transitioning to psychosis but only less than half remit over time. Sustained clinical attention should be provided in the longer term to monitor these outcomes.