One-third of schizophrenia patients show a lack of response to conventional antipsychotic drugs because of adverse effects and limited efficacy. Emerging treatments target muscarinic and nicotinic receptors, leveraging cholinergic dysfunction implicated in the pathophysiology of schizophrenia.

To evaluate the efficacy and safety of cholinergic modulators in schizophrenia.

Reviewers extracted data from clinical trials sourced via MEDLINE/PubMed, Embase, Scopus, Cochrane databases and registries. Quality was assessed with a risk-of-bias tool and a random-effects model estimated effect size. Subgroup analysis, meta-regression and sensitivity analysis were performed as needed, adhering to PRISMA guidelines.

A total of 30 randomised controlled trials (3128 participants) tested cholinergic modulators as monotherapy or adjunct therapy. They did not significantly improve Positive and Negative Syndrome Scale (PANSS) total scores (standardised mean difference (SMD): −0.38; 95% CI: −0.93, 0.18; moderate certainty evidence) but did improve negative symptom scores (SMD: −0.42; 95% CI: −0.59, −0.25; moderate certainty evidence). Muscarinic agonists improved total (SMD: −0.57; 95% CI: −0.72, −0.42), positive (SMD: −0.58; 95% CI: −0.73, −0.43) and negative symptoms of PANSS (SMD: −0.40; 95% CI: −0.59, −0.21), as well as Clinical Global Impression-severity (CGI-S) (SMD: −0.48; 95% CI: −0.65, −0.31). Nicotinic agonists aided negative symptoms (SMD: −0.28; 95% CI: −0.47, −0.09) and CGI-S (SMD: −1.31; 95% CI: −2.38, −0.24). Adverse events were higher (odds ratio: 1.21; 95% CI: 0.94, 1.56) in the experimental group.

Cholinergic modulators significantly improve negative symptoms, with muscarinic agonists showing improvement across symptom domains and severity, without notable differences in adverse effects from placebo. Most studies were at low bias risk; evidence quality ranged from very low to moderate.

Schizophrenia is a multifactorial disorder with a range of risk factors. Dysregulation in the systems involved in the stress response is a key component of its pathophysiology. Individuals at risk of developing schizophrenia exhibit hyperreactivity to stress and altered cognitive performance, both known as vulnerability markers. This study aims to determine whether stimulation of the prefrontal cortex can reduce reactivity to stress in unaffected siblings of patients with schizophrenia.

In a randomized, sham-controlled trial, 27 participants were assigned to receive either active (n = 14) or sham (n = 13) transcranial direct current stimulation (tDCS) over the prefrontal cortex for 30 min during exposure to an acute stressor. The stress response was measured biologically, via salivary cortisol levels, and cognitively, through a reality monitoring task, which serves as an intermediate cognitive vulnerability marker.

In contrast to the sham condition, active stimulation significantly reduced cortisol release in response to stress (F(9,216) = 1.972; p = 0.04) and prevented stress-induced impairment in reality monitoring (F(1,23) = 9.954; p = 0.004).

These findings suggest that tDCS should be a promising tool for reducing stress-induced biological and cognitive reactivity in a population at risk of schizophrenia.

Sleep problems are common in psychotic disorders and are associated with worse quality of life and disease prognosis. Genome-wide association studies (GWAS) have revealed genetic influences for schizophrenia and sleep, but polygenic scores (PGSs) for sleep traits have not been evaluated systematically in patients with psychotic disorders.

This study investigated the associations between PGSs for sleep traits (insomnia, PGSINS; sleep duration, PGSSD; short sleep duration, PGSSS; long sleep duration; PGSLS), diurnal preference (eveningness, PGSME), and schizophrenia (PGSSZ) with clinical features of psychotic disorders in the Finnish SUPER study comprising 8,232 patients with psychotic disorders. The measures included self-reported sleep and well-being, cognitive assessments, clozapine use, and functional outcomes. Using FinnGen data of 356,077 individuals, we analyzed the distributions of PGSs in psychotic and bipolar disorders and the general population.

PGSINS associated with more sleep problems and worse well-being (e.g. worse health-related quality of life [β = −0.07, CI = −0.09, −0.05, p < .001]). High PGSSZ is associated with better sleep quality, worse clinical outcomes, and performance in cognitive tests (e.g. more errors in paired-associated learning [β = 0.07, CI = 0.04, 0.09, p < .001]). PGSINS was higher in affective psychotic and bipolar disorders, while PGSSD and PGSME were higher in schizophrenia as compared with individuals with no psychiatric disorders.

Genetic risks for sleep and diurnal preference vary between non-affective psychosis, affective psychosis, and the general population. The findings in this study emphasize the heterogeneity in genetic etiology of the objective features of disease severity and the more subjective measures related to well-being and self-reported measures of sleep.

A systematic review and meta-analysis was conducted to investigate the prevalence and antecedents/outcomes of loneliness and social isolation among individuals with severe mental disorders (SMD), such as schizophrenia, schizoaffective disorder, bipolar disorder or major depressive disorder.

Five well-known electronic databases (PubMed, PsycINFO, CINAHL, Web of Science and Scopus) were searched (plus a hand search). Observational studies that report the prevalence and, if available, antecedents and consequences of loneliness/isolation among individuals with SMD were included. Key characteristics were extracted, and a meta-analysis was performed. Our systematic review was preregistered on PROSPERO (ID: CRD42024559043). The PRISMA guidelines were followed. The Joanna Briggs Institute (JBI) standardized critical appraisal tool developed for prevalence studies was applied to assess the quality of the included studies.

The initial search yielded 4506 records, and after duplicate removal and screening, a total of 10 studies were finally included. The studies included used data from Europe, Asia, North America, and Oceania. Two studies employed a longitudinal design, while all other studies had a cross-sectional design. Most of the studies included between 100 and 500 individuals with SMD. All studies involved both male and female participants, with women typically comprising about 40% of the sample. The average age of participants often ranged from approximately 30 to 40 years. The estimated prevalence of loneliness was 59.1% (95% CI: 39.6% to 78.6%, I2 = 99.3, P < .001) among individuals with any diagnosis of SMD. Furthermore, the estimated prevalence of objective social isolation was 63.0% (95% CI: 58.6% to 67.4%) among individuals with schizophrenia or schizophrenia spectrum disorder. The quality of the studies was moderate to good. Subjective well-being and depressive symptoms in particular were found to contribute to loneliness in the included studies.

The present systematic review with meta-analysis identified high levels of loneliness and objective social isolation among those with SMD. These findings stress the importance of monitoring and addressing social needs in this vulnerable group, which may have a positive effect on the life quality of individuals with SMD. Future research in neglected regions (e.g. South America and Africa) is recommended. Different diagnoses within severe mental disorders should be distinguished in future studies. Furthermore, additional longitudinal studies are required to explore the antecedents and consequences of loneliness and social isolation among individuals with SMD.

Suicide remains a major risk factor for individuals suffering from schizophrenia and its prodromal state (i.e., Ultra-High Risk for Psychosis). However, less is known about the prevalence of suicidal behaviour among the adolescent and youth UHR population, a demographic vulnerable to the psychosocial and environmental risk factors of suicide. This review aims to synthesise existing literature on the prevalence of suicidal ideation and behaviour in the adolescent and youth at Ultra-High Risk for Psychosis (UHR), and the associations between suicidal behaviour and its correlates.

The databases PsycINFO, PubMed, Embase, Cochrane Library, Web of Science, and Scopus were accessed up to July 2024. A meta-analysis of prevalence was subsequently performed for lifetime suicidal ideation, lifetime non-suicidal self-injury, lifetime suicidal attempt, and current suicidal ideation. A narrative review was also carried out for the correlates of suicidal behaviour amongst adolescents and youth in the UHR population.

Studies were included in this meta-analysis. Meta-analysis revealed a high prevalence of lifetime suicidal ideation (58%), lifetime non-suicidal self-injury (37%), lifetime suicidal attempt (25%), and current (2 week) suicidal ideation (56%). The narrative review revealed that a personal transition to psychosis and a positive family history of psychosis were associated with suicidal attempts, while depression was associated with both suicidal attempts and suicidal ideation.

The prevalence of suicidal ideation and behaviour among UHR adolescents and youth is high and comparable to that of the general UHR population. Existing measures that mitigate suicide risk in the general UHR population should be adopted for the youth context.

Glucuronic acid (GlcA) is crucial in the glucuronidation pathway, facilitating the metabolism and elimination of various substances and drugs. Recent studies have noted elevated GlcA levels in patients with schizophrenia (SCZ) compared with healthy individuals. However, it remains unclear whether this elevation contributes to SCZ pathophysiology or results from medication effects.

This study investigated the relationship between peripheral GlcA levels and clinical characteristics in patients with SCZ and assess whether these associations persist independently of psychotropic medication effects to provide insight into the potential role of GlcA in the pathophysiology of SCZ.

Plasma GlcA levels were analysed in 218 patients with SCZ, examining their association with clinical features. The correlation between GlcA levels and symptom severity, assessed using the Positive and Negative Syndrome Scale (PANSS), was analysed in 35 patients. In addition, multiple regression analysis was conducted to adjust for age and psychotropic medication effects.

Significant correlations were observed between GlcA levels and PANSS scores for negative symptoms, general psychopathology and total scores. After adjustment for age and psychotropic medications, significant correlations between GlcA levels and PANSS scores persisted for negative symptoms (adjusted β [95% CI], 13.926 [2.369, 25.483]) and general psychopathology (adjusted β [95% CI], 19.437 [3.884, 34.990]), while the total score was no longer significant (adjusted β [95% CI], 34.054 [–0.517, 68.626]).

Elevated GlcA levels in patients with SCZ are associated with specific symptom severity irrespective of the medication dose, suggesting a potential role of GlcA in SCZ pathophysiology.

Findings from contemporary clinical trials suggest that psychedelics are generally safe and may be effective in the treatment of various psychiatric disorders. However, less is known about the risks associated with psychedelic use outside of medically supervised contexts, particularly in populations that are typically excluded from participation in clinical trials.

Using a preregistered longitudinal observational research design with a purposive sample of US residents between 18 and 50 years old (N=21,990), we investigated associations between self-reported naturalistic psychedelic use and psychotic and manic symptoms, with emphasis on those with psychiatric histories of schizophrenia or bipolar I disorder.

The follow-up survey was completed by 12,345 participants (56% retention), with 505 participants reporting psychedelic use during the 2-month study period. In covariate-adjusted regression models, psychedelic use during the study period was associated with increases in the severity of psychotic and manic symptoms. However, such increases were only observed for those who reported psychedelic use in an illegal context. While increases in the severity of psychotic symptoms appeared to depend on the frequency of use and the intensity of challenging psychedelic experiences, increases in the severity of manic symptoms appeared to be moderated by a personal history of schizophrenia or bipolar I disorder and the subjective experience of insight during a psychedelic experience.

The findings suggest that naturalistic psychedelic use specifically in illegal contexts may lead to increases in the severity of psychotic and manic symptoms. Such increases may depend on the frequency of use, the acute subjective psychedelic experience, and psychiatric history.

Recent studies have increasingly utilized gradient metrics to investigate the spatial transitions of brain organization, enabling the conversion of macroscale brain features into low-dimensional manifold representations. However, it remains unclear whether alterations exist in the cortical morphometric similarity (MS) network gradient in patients with schizophrenia (SCZ). This study aims to examine potential differences in the principal MS gradient between individuals with SCZ and healthy controls and to explore how these differences relate to transcriptional profiles and clinical phenomenology.

MS network was constructed in this study, and its gradient of the network was computed in 203 patients with SCZ and 201 healthy controls, who shared the same demographics in terms of age and gender. To examine irregularities in the MS network gradient, between-group comparisons were carried out, and partial least squares regression analysis was used to study the relationships between the MS network gradient-based variations in SCZ, and gene expression patterns and clinical phenotype.

In contrast to healthy controls, the principal MS gradient of patients with SCZ was primarily significantly lower in sensorimotor areas, and higher in more areas. In addition, the aberrant gradient pattern was spatially linked with the genes enriched for neurobiologically significant pathways and preferential expression in various brain regions and cortical layers. Furthermore, there were strong positive connections between the principal MS gradient and the symptomatologic score in SCZ.

These findings showed changes in the principal MS network gradient in SCZ and offered potential molecular explanations for the structural changes underpinning SCZ.

Schizophrenia is a chronic condition that requires long-term management. Quality of life is an important outcome measure for individuals diagnosed with schizophrenia; it can be tracked over time allowing evaluation of whether interventions lead to sustainable improvements. Nutrition and dietary interventions are an underutilized treatment for tackling the metabolic consequences of mental illness, which is now recognized as having increased importance in the management of schizophrenia. This study examines the impact of nutrition and dietary interventions on quality of life outcomes for those with schizophrenia.

A systematic review of the literature was conducted, assessing the impact of nutritional interventions on quality of life outcomes in individuals with a diagnosis of schizophrenia.

A total of 982 articles were screened, of which nine articles met the inclusion criteria. Quality of life measures varied across studies, which made comparison across studies challenging. Previous studies had relatively small sample sizes and did not have long follow-up durations. Some of the studies found that dietary interventions such as counselling, weight management programs, food diaries and nutritional education improved quality of life, whereas others did not detect any effect.

The review provides preliminary evidence that nutrition and dietary interventions may benefit quality of life among individuals with schizophrenia. There were however substantial limitations in studies highlighting the need for further research. The paper also highlights the need to standardize assessment tools for future quality-of-life research.

It is widely known that people with a severe and persistent mental illness (SPMI) are more at risk of poor physical health outcomes because of disparities in healthcare access and provision. Less is known about the quality of end-of-life (EoL) care in people with SPMI who have a life-limiting disease.

A comprehensive and systematic literature search in PubMed, Embase, Web of Science, Scopus, and CINAHL electronic databases (from inception to November 2023) was conducted, without language restriction, for reviews on EoL care and/or palliative sedation for people with SPMI and a life-limiting disease. A critical appraisal of the selected reviews was performed. Data were analyzed according to the four principles of biomedical ethics.

Ten reviews were included. These show that people with SPMI are at risk of suboptimal EoL care. Stigma among healthcare professionals, lack of integrated care policies, absence of advanced care planning, and insufficient expertise and training in palliative care of psychiatrists have been identified as key challenges to the provision of adequate EoL care for people with SPMI. No data were found about palliative sedation.

To optimize palliative and EoL care for SPMI patients with a life-limiting disease, a policy of coordinated and integrated mental and physical healthcare is needed. Moreover, education and training initiatives to reduce stigma and discrimination among all healthcare workers and to enhance palliative care skills in psychiatrists should be offered. Finally, more research is needed on EoL particularly on palliative sedation for people with SPMI and a life-limiting disease.

Catatonia in psychotic patients presents unique challenges. While antipsychotics are the cornerstone of schizophrenia treatment, their use in catatonic patients is sometimes discouraged for fear of worsening the signs. Reports on the successful use of second-generation antipsychotics have been published. We conducted a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines to describe the outcomes of antipsychotic-treated catatonic events.

We searched Medline and Web of Science databases from 2000 to 2023 using search terms including “catatonia” and “antipsychotic agents” for all original peer-reviewed articles, including clinical trials, observational studies, and case-reports. We included antipsychotic-treated catatonic events and extracted data on patient characteristics, pharmacological context, agent involved, and treatment outcomes for each antipsychotic trial.

After screening 6,219 records, 79 full-text articles were included. Among them, we identified 175 antipsychotic trials (in 110 patients). Only 41.1% of the patients benefited from a previous benzodiazepine trial. Antipsychotic use was considered beneficial in 60.0% of the trials, neutral in 29.1%, and harmful in 10.9%. Trials tended to be reported as beneficial for amisulpride, clozapine, and risperidone, equivocal for aripiprazole and olanzapine, and mostly detrimental for haloperidol and quetiapine. Psychotic disorders were the most common underlying etiology (65.8%).

Antipsychotics could be an option in the treatment of catatonia in psychotic patients. However, with few exceptions, we found non-beneficial outcomes with all second-generation antipsychotics in varying proportions in this largest review to date. Although olanzapine is widely used, it is associated with mitigated reported outcomes.

Obsessive-compulsive symptoms (OCS) emerge in a significant proportion of clozapine-treated schizophrenia patients, affecting social functioning and increasing depressive symptoms. This study investigates the underexplored cognitive mechanisms of clozapine-induced OCS, particularly focusing on dysfunctional checking behavior.

Clinical and cognitive profiles of OCS and their relationship to dysfunctional checking were investigated using a novel checking paradigm (image verification task or IVT) in four groups: clozapine-treated schizophrenia patients with clozapine-induced OCS (SCZ-OCS, n = 21) and without (SCZ-only, n = 15), patients with obsessive-compulsive disorder (OCD, n = 32) and IQ-matched healthy volunteers (HV, n = 30).

Only SCZ-OCS patients showed a distinctive pattern of dysfunctional checking on the IVT. Compared with SCZ-OCS, SCZ-only patients exhibited functional checking while having equivalent deficits in executive cognition, clozapine dose, and treatment duration, though with less severe positive and depressive symptoms. In SCZ-OCS, dysfunctional checking was positively correlated with clozapine dose and working memory performance. By contrast, OCD patients’ checking was positively related to intolerance of uncertainty. Checking in the OCD and SCZ-OCS groups was positively correlated with YBOCS-compulsion.

This study is the first to compare the distinct cognitive and clinical profiles of SCZ-OCS, SCZ-only, and OCD, with a focus on checking behavior, a major symptom in clozapine-treated patients. We introduced a novel and sensitive measure for checking, which showed dysfunctional checking only in SCZ-OCS patients treated with clozapine. These findings indicate that a subset of patients with schizophrenia with more severe positive symptoms and cognitive deficits are especially susceptible to OCD symptoms when treated with clozapine.