Exploring causal mechanisms of psychosis risk.

Robust epidemiological evidence of risk and protective factors for psychosis is essential to inform preventive interventions. Previous evidence syntheses have classified these risk and protective factors according to their strength of association with psychosis. In this critical review we appraise the distinct and overlapping mechanisms of 25 key environmental risk factors for psychosis, and link these to mechanistic pathways that may contribute to neurochemical alterations hypothesised to underlie psychotic symptoms. We then discuss the implications of our findings for future research, specifically considering interactions between factors, exploring universal and subgroup-specific factors, improving understanding of temporality and risk dynamics, standardising operationalisation and measurement of risk and protective factors, and developing preventive interventions targeting risk and protective factors.

Robust and replicable functional brain signatures of 22q11.2 deletion syndrome and associated psychosis: a deep neural network-based multi-cohort study.

A major genetic risk factor for psychosis is 22q11.2 deletion (22q11.2DS). However, robust and replicable functional brain signatures of 22q11.2DS and 22q11.2DS-associated psychosis remain elusive due to small sample sizes and a focus on small single-site cohorts. Here, we identify functional brain signatures of 22q11.2DS and 22q11.2DS-associated psychosis, and their links with idiopathic early psychosis, using one of the largest multi-cohort data to date. We obtained multi-cohort clinical phenotypic and task-free fMRI data from 856 participants (101 22q11.2DS, 120 idiopathic early psychosis, 101 idiopathic autism, 123 idiopathic ADHD, and 411 healthy controls) in a case-control design. A novel spatiotemporal deep neural network (stDNN)-based analysis was applied to the multi-cohort data to identify functional brain signatures of 22q11.2DS and 22q11.2DS-associated psychosis. Next, stDNN was used to test the hypothesis that the functional brain signatures of 22q11.2DS-associated psychosis overlap with idiopathic early psychosis but not with autism and ADHD. stDNN-derived brain signatures distinguished 22q11.2DS from controls, and 22q11.2DS-associated psychosis with very high accuracies (86-94%) in the primary cohort and two fully independent cohorts without additional training. Robust distinguishing features of 22q11.2DS-associated psychosis emerged in the anterior insula node of the salience network and the striatum node of the dopaminergic reward pathway. These features also distinguished individuals with idiopathic early psychosis from controls, but not idiopathic autism or ADHD. Our results reveal that individuals with 22q11.2DS exhibit a highly distinct functional brain organization compared to controls. Additionally, the brain signatures of 22q11.2DS-associated psychosis overlap with those of idiopathic early psychosis in the salience network and dopaminergic reward pathway, providing substantial empirical support for the theoretical aberrant salience-based model of psychosis. Collectively, our findings, replicated across multiple independent cohorts, advance the understanding of 22q11.2DS and associated psychosis, underscoring the value of 22q11.2DS as a genetic model for probing the neurobiological underpinnings of psychosis and its progression.

Source-based morphometry reveals structural brain pattern abnormalities in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism.

Uso de cannabis en jóvenes hospitalizados por un primer episodio de psicosis: un estudio caso-control

Background: Cannabis use among young people in Chile has increased significantly in the last years. There is a consistent link between cannabis and psychosis. Aim: To compare cannabis use in patients with a first episode of psychosis and healthy controls. Material and Methods: We included 74 patients aged 20 ± 3 years (78% males) admitted to hospital with a first episode of psychosis and a group of 60 healthy controls aged 23 ± 4 years (63% males). Cannabis consumption was assessed, including age of first time use and length of regular use. Results: Patients with psychosis reported a non-significantly higher frequency of life-time cannabis use. Patients had longer periods of regular cannabis use compared with healthy subjects (Odds ratio [OR] 2.4; 95% confi-dence intervals [CI] 1.14-5.05). Patients also used cannabis for the first time at an earlier age (16 compared with 17 years, p < 0.0). The population attributable fraction for regular cannabis use associated with hospital admissions due to psychosis was 17.7% (95% CI 1.2-45.5%). Conclusions: Cannabis use is related to psychosis in this Chilean group of patients. This relationship is stronger in patients with early exposure to the drug and longer the regular use. One of every five admissions due to psychosis is associated with cannabis consumption. These data should influence cannabis legisla-tion and the public policies currently being discussed in Chile.

Antipsicóticos de primera y segunda generación en esquizofrenia: eficacia, efectividad y efecto de la dosis utilizada / First and second generation antipsychotics in schizophrenia: efficacy, effectiveness and effect of the dose used

Después de varias décadas de desarrollo de los fármacos antipsicóticos, la esquizofrenia sigue siendo en gran medida una enfermedad crónica con muchos pacientes que experimentan una mala calidad de vida. En este contexto, la aparición de los llamados antipsicóticos de segunda generación fue recibida con gran entusiasmo. Los clínicos esperaban que los nuevos antipsicóticos causaran no solamente menos efectos secundarios motores que los más antiguos, tal como la clorpromazina, sino también que mejoraran los síntomas y la funcionalidad general de los pacientes. Este artículo, de carácter narrativo, revisa cómo inicialmente la evidencia de un gran número de ensayos controlados aleatorios pareció favorecer muchas de estas suposiciones. Esta visión, sin embargo, no era universal, y algunos investigadores destacaron el potencial efecto del diseño de los estudios en los resultados. Un aspecto importante dice relación con la dosis utilizada de antipsicóticos de primera generación, siendo aquellos ensayos que usaron mayores dosis los que apoyaron el uso de antipsicóticos de segunda generación. Esta controversia se resolvió después de la publicación de tres estudios a gran escala, que incluían pacientes menos seleccionados y que enfocaban los resultados a largo plazo en un entorno clínico más "típico", los cuales no encontraron diferencias significativas entre los dos tipos de antipsicóticos. Desde entonces, las discusiones sobre la elección de los antipsicóticos han girado en torno a otros factores tales como los efectos secundarios, más que en su capacidad para controlar los síntomas.(AU)

After several decades of antipsychotic medication development, schizophrenia has largely remained a chronic disease with many patients experiencing poor quality of life. In this context, the appearance of so-called second generation antipsychotics was received with great enthusiasm. Clinicians hoped that the new antipsychotics would not only cause less motor side effects than older ones such as Chlorpromazine, but also improve patients' symptoms and overall functioning. In this narrative article we review how initially the vidence of a large number of randomized controlled trials appeared to favour many of these claims. This view was not universal though, and some researchers highlighted the potential effect of some design aspects of the trials in the results. A particular concern related to the dose of first generation antipsychotic used, with trials favouring second generation frequently using higher doses. This controversy was resolved after the publication of three large studies, including less selected patients and looking at longer-term outcomes in a more "typical" clinical setting, which failed to find significant differences between the two types of antipsychotics. Since then, discussions about the choice of antipsychotic revolve more around other factors such as side-effects than their capacity to control symptom.(AU)