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.

Impairment in both psychosocial functioning and neurocognition (NC) performance is present in bipolar disorder (BD) yet the role of sex differences in these deficits remains unclear. The present systematic review and meta-analysis examined whether males and females with BD demonstrate differences in psychosocial functioning and NC performance.

The Cochrane Library, EMBASE, PsycINFO, PubMed, Scopus, and Web of Science databases were systematically searched from inception until November 20, 2023.

Twenty studies published between 2005 and 2023 with a total sample size of 2286 patients with BD were included. A random effects meta-analysis revealed a statistically significant result with a small effect (SMD = 0.313) for sex differences in verbal learning and memory as well as visual learning and memory (SMD = 0.263). Females outperformed males in both domains. No significant sex differences were observed for any other NC outcome or psychosocial functioning. High heterogeneity and differences in assessment scales used should be considered when interpreting these findings, given their potential impact on results.

Future research should adopt a more homogenous, standardized approach using longitudinal designs to gain a clearer insight into sex differences in this population. This approach so may increase the use of preventative therapeutic options to address the difficult clinical challenge of reaching cognitive and functional recovery.

Emerging evidence suggests a potential association between “leaky gut syndrome” and low-grade systemic inflammation in individuals with psychiatric disorders, such as schizophrenia. Gut dysbiosis could increase intestinal permeability, allowing the passage of toxins and bacteria into the systemic circulation, subsequently triggering immune-reactive responses. This study delves into understanding the relationship between plasma markers of intestinal permeability and symptom severity in schizophrenia. Furthermore, the influence of lifestyle habits on these intestinal permeability markers was determined.

Biomarkers of intestinal permeability, namely lipopolysaccharide-binding protein (LBP), lipopolysaccharides (LPS), and intestinal fatty acid binding protein (I-FABP), were analyzed in 242 adult schizophrenia patients enrolled in an observational, cross-sectional, multicenter study from four centers in Spain (PI17/00246). Sociodemographic and clinical data were collected, including psychoactive drug use, lifestyle habits, the Positive and Negative Syndrome Scale to evaluate schizophrenia symptom severity, and the Screen for Cognitive Impairment in Psychiatry to assess cognitive performance.

Results revealed elevated levels of LBP and LPS in a significant proportion of patients with schizophrenia (62% and 25.6%, respectively). However, no statistically significant correlation was observed between these biomarkers and the overall clinical severity of psychotic symptoms or cognitive performance, once confounding variables were controlled for. Interestingly, adherence to a Mediterranean diet was negatively correlated with I-FABP levels (beta = −0.186, t = −2.325, p = 0.021), suggesting a potential positive influence on intestinal barrier function.

These findings underscore the importance of addressing dietary habits and promoting a healthy lifestyle in individuals with schizophrenia, with potential implications for both physical and psychopathological aspects of the disorder.

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

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

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

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

Childhood adversity and cannabis use are considered independent risk factors for psychosis, but whether different patterns of cannabis use may be acting as mediator between adversity and psychotic disorders has not yet been explored. The aim of this study is to examine whether cannabis use mediates the relationship between childhood adversity and psychosis.

Data were utilised on 881 first-episode psychosis patients and 1231 controls from the European network of national schizophrenia networks studying Gene–Environment Interactions (EU-GEI) study. Detailed history of cannabis use was collected with the Cannabis Experience Questionnaire. The Childhood Experience of Care and Abuse Questionnaire was used to assess exposure to household discord, sexual, physical or emotional abuse and bullying in two periods: early (0–11 years), and late (12–17 years). A path decomposition method was used to analyse whether the association between childhood adversity and psychosis was mediated by (1) lifetime cannabis use, (2) cannabis potency and (3) frequency of use.

The association between household discord and psychosis was partially mediated by lifetime use of cannabis (indirect effect coef. 0.078, s.e. 0.022, 17%), its potency (indirect effect coef. 0.059, s.e. 0.018, 14%) and by frequency (indirect effect coef. 0.117, s.e. 0.038, 29%). Similar findings were obtained when analyses were restricted to early exposure to household discord.

Harmful patterns of cannabis use mediated the association between specific childhood adversities, like household discord, with later psychosis. Children exposed to particularly challenging environments in their household could benefit from psychosocial interventions aimed at preventing cannabis misuse.

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.

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

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

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

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

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

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

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

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

Around 30% of patients with schizophrenia are considered treatment resistant (TRS). Only around 40% of TRS patients respond to clozapine. Long acting injectable antipsychotics could be a useful augmentation strategy for nonresponders.

We conducted a multicenter, observational, naturalistic, retrospective, 6-month mirror-image study to evaluate the efficacy and tolerability of clozapine and paliperidone palmitate association in 50 patients with TRS and other psychotic disorders. Clinical outcomes and side effects were systematically assessed.

Six months after starting the combined treatment, participants showed a significant relief of symptoms, decreasing the Brief Psychiatric Rating Scale total score from 18.32 ± 7.71 to 7.84 ± 5.16 (p < 0.001). The number of hospitalizations, the length of hospital stays and the number of visits to emergency services also decreased, while an increase of the functionality was observed (Personal and Social Performance total score increased from 46.06 ± 118.7 to 60.86 ± 18.68, p < 0.001). There was also a significant decrease in the number and severity of side effects with the combination therapy, decreasing the Udvalg for Kliniske Undersogelser total score from 10.76 ± 8.04 to 8.82 ± 6.63 (p = 0.004).

This study provides the first evidence that combining clozapine with paliperidone palmitate in patients with TRS and other psychotic disorders could be effective and safe, suggesting further research with randomized controlled trials of augmentation strategies for clozapine nonresponder patients.

Patients with psychotic disorders such as schizophrenia show a variable response to antipsychotic treatments. Around 30% of patients are considered treatment resistant, indicated by insufficient symptom control to at least two different drugs. In these resistant cases, clozapine should be indicated, as it has shown to be superior to other options. However, only 40% of patients respond to clozapine, being necessary to establish which treatments could best potentiate clozapine action. Combining clozapine with long acting injectable antipsychotics, and particularly paliperidone palmitate, could be a useful strategy. We conducted a multicenter study of 50 patients with treatment-resistant schizophrenia and other psychotic disorders comparing the efficacy and tolerability in the 6 month-period prior and after starting the clozapine and paliperidone palmitate association. Our study suggests that this combination could be effective and safer, laying the groundwork for future clinical trials with this combination.

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

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

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

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

Observational studies have reported earlier onset of psychosis in schizophrenic patients with a history of cannabis use. Earlier age of onset of schizophrenia has been associated with a poorer outcome. We aimed to examine whether cannabis use determined an earlier onset of schizophrenia in a sample of first episode patients, in an area with one of Europe's highest rates of cannabis use.

116 subjects with first episode psychosis and subsequent diagnosis of schizophrenia (after a 12-month follow-up) were included Age at first antipsychotic treatment (A1T) was used as proxy for age of psychosis onset, and acted as dependent variable for the statistical analysis. Cannabis use was evaluated retrospectively, and divided into three groups according to peak frequency (never, sporadic/frequent, daily).

46 (39.7%) subjects had never used cannabis, 23 (19.9%) had done so sporadically/frequently, and 47 (40.5%) daily. A1T differed between the three groups (mean, in years and [SD]: 27.0 [4.94]; 25.7 [4.44] and 24.5 [4.36]; p = 0.033) and diminished as cannabis use increased (linear tendency; p = 0.009). Post-hoc analysis showed that cannabis use (irrespective of frequency) was significantly associated with decrease in A1T (p = 0.033), as shown by the first contrast [1 −1/2 −1/2]. Post-hoc contrast showed that cannabis users had a significantly lower age of onset of psychosis (mean decrease, in years: 1.93; CI (confidence interval) 95%: 0.17–3.70; p = 0.033).

Cannabis use was significantly associated with a decrease in age of onset of schizophrenia. Age of onset of the disease correlated with frequency of cannabis use.

Mixed bipolar states are not infrequent and may be extremely difficult to treat. Lithium, anticonvulsants including valproate and carbamazepine, and antipsychotics such as olanzapine, ziprasidone, and aripiprazole have been reported to be at least partially effective in controlled clinical trials, but many patients do not respond to pharmacological approaches. Electroconvulsive therapy has been tested to be efficacious for the treatment of both manic and depressive episodes, but much less evidence is available with regards to mixed states. The aim of the review was to report the available evidence for the use of electroconvulsive therapy in mixed bipolar states.

A systematic review of the literature on treatment of mixed states, focused on electroconvulsive therapy, was made, beginning in August 1992 and ending in March 2007. The key words were “electroconvulsive therapy” and “mixed bipolar”.

Only three studies met the required quality criteria and were included. This literature suggests that ECT is an effective, safe, and probably underutilized treatment of mixed states. Recent technical developments have made ECT more friendly, tolerable, and safe. Potential alternatives, such as vagus nerve stimulation, deep brain stimulation, or transcranial stimulation, are still far to be proved as effective as ECT.

Daily use of high-potency cannabis has been reported to carry a high risk for developing a psychotic disorder. However, the evidence is mixed on whether any pattern of cannabis use is associated with a particular symptomatology in first-episode psychosis (FEP) patients.

We analysed data from 901 FEP patients and 1235 controls recruited across six countries, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. We used item response modelling to estimate two bifactor models, which included general and specific dimensions of psychotic symptoms in patients and psychotic experiences in controls. The associations between these dimensions and cannabis use were evaluated using linear mixed-effects models analyses.

In patients, there was a linear relationship between the positive symptom dimension and the extent of lifetime exposure to cannabis, with daily users of high-potency cannabis having the highest score (B = 0.35; 95% CI 0.14–0.56). Moreover, negative symptoms were more common among patients who never used cannabis compared with those with any pattern of use (B = −0.22; 95% CI −0.37 to −0.07). In controls, psychotic experiences were associated with current use of cannabis but not with the extent of lifetime use. Neither patients nor controls presented differences in depressive dimension related to cannabis use.

Our findings provide the first large-scale evidence that FEP patients with a history of daily use of high-potency cannabis present with more positive and less negative symptoms, compared with those who never used cannabis or used low-potency types.

Cingulate dysfunction has been reported in schizophrenia. Although the paracingulate sulcus (PCS) is known to be asymmetric in healthy people, little information is available about its morphology in schizophrenia.

To search for morphological anomalies of the PCS in men with early-onset schizophrenia.

The PCS was examined in magnetic resonance images of the brains of men with schizophrenia and 100 healthy men.

A significant asymmetry was found in the brains of healthy volunteers, whose sulci were more frequent and more marked in the left hemisphere. In contrast, the sulcus was as frequent in the right as in the left hemisphere in the patient group. Moreover, patients displayed significantly more rightward asymmetry, and overall less-asymmetrical patterns than the comparison group.

Since the PCS has developed at 36 weeks of gestation, these findings suggest an impaired maturation of the cingulate region during the third trimester.