Psychosis is a complex brain disorder with diverse biological subtypes influenced by various pathogenic mechanisms, which can affect treatment efficacy. The ANR(Attenuated Niacin Response) subtype is characterized by pronounced negative symptoms and functional impairments, suggesting a distinct clinical profile. However, research on the cognitive characteristics associated with the ANR subtype in drug-naïve first-episode psychosis(FEP) patients remains limited.

This observational study involved 54 FEP patients and 52 healthy controls(HC). Clinical psychopathology was assessed using the Positive and Negative Syndrome Scale(PANSS), while cognitive performance was evaluated through the Chinese version of the MATRICS Consensus Cognitive Battery(MCCB). Additionally, niacin response was measured using aqueous methylnicotinate patches, with responses quantified to classify participants into ANR or normal niacin response (NNR) groups.

Among the FEP patients, 25.9 % were classified as having ANR, significantly higher than the 7.7 % in the HC group (χ 2  = 6.247, p = 0.012). The ANR group exhibited more severe negative symptoms and higher total PANSS scores compared to the NNR group, with significant differences in cognitive performance on the Trail Making test and the Brief Visuospatial Memory Test-Revised. Correlation analyses revealed a significant positive relationship between overall symptom severity and niacin response, as well as between cognitive performance and niacin response, particularly for the Trail Making and Symbol coding tests.

This study demonstrates that the ANR subtype in first-episode psychosis is linked to more severe negative symptoms and cognitive impairments. Targeted assessments and interventions for patients with ANR may improve treatment outcomes and enhance understanding of cognitive dysfunction in psychotic disorders.

Negative symptoms in schizophrenia spectrum are associated with minimal treatment responses. The search for effective treatments is potentially hampered by heterogenous study-designs and sample characteristics depending on the intervention category. This PRISMA-compliant systematic review/synthesis aims to describe the literature on negative symptoms interventions for schizophrenia spectrum disorders by comparing 12 study design, demographical and clinical variables in different intervention categories: antipsychotics (AP), other pharmacological agents (OPA), brain stimulation (BS), psychological/psychosocial (PSI), lifestyle (LS), mixed interventions. Kruskal-Wallis and Chi-square tests measured differences between intervention-groups. Out of 19,935 articles, 489 (AP=149/OPA=187/BS=49/PSI=79/LS=19/mixed=6) were selected for data extraction. Concerning study designs, AP had the largest average arm size (mean ± SD=91.1 ± 122.8participants), OPA the highest double/triple-blinding (97.9 %) rates, PSI the longest follow-up (26.7 ± 21.8weeks). Age/gender demographical differences were significant but of negligible magnitude. OPA illness duration (14.8 ± 9.0years) was longer compared to AP (11.4 ± 6.7years). Positive and Negative Syndrome Scale (PANSS) negative scores were milder in PSI (18.6 ± 6.9) compared to AP/OPA/BS (23.8 ± 6.4/23.4 ± 4.9/24.2 ± 9.2). PANSS total scores were worse in AP (83.6 ± 18.2) than in OPA/BS/PSI (77.1 ± 20.5/75.5 ± 14.7/67.0 ± 23.3). The same was true for dropout rates (AP=25.5 %, OPA/BS/PSI=14.3/9.7/14.5 %). Prevalent treatment as usual was "none" for AP (36.7 %) and "antipsychotic" for other categories (42.3-82.8 %). Implementing cross-over, factorial or multi-arm designs may increase the comparability between studies investigating different intervention categories. Concerning clinical differences, reporting individual treatments at baseline and clinical severity, evaluating cognitive profiles and considering patients' perspectives will allow to better understand the efficacy of the available treatments and develop tailored interventions.

Negative symptoms of schizophrenia (NSS) carry a substantial burden, and there are no treatments currently approved for NSS. The efficacy of pimavanserin, a selective 5-HT2A inverse agonist and antagonist, in treating NSS was assessed.

ADVANCE-2 was a phase 3, randomized, double-blind, placebo-controlled study of pimavanserin in patients with schizophrenia and predominantly negative symptoms. Patients were randomized (1:1) to receive pimavanserin (34 mg/day) or placebo alongside ongoing background antipsychotic medication. Eligible adults were aged 18-55 years and had access to a caregiver. The primary and key secondary endpoints were the change from baseline to week 26 in the Negative Symptom Assessment-16 (NSA-16) total score and Clinical Global Impression-Schizophrenia Scale-Severity (CGI-SCH-S) negative symptom score, respectively.

Of the 454 randomized patients, 71 (39 placebo; 32 pimavanserin) discontinued and 383 (188 placebo; 195 pimavanserin) completed the study. The safety and full analysis sets comprised 453 and 446 patients, respectively. The NSA-16 change from baseline to week 26 was not significantly different between groups (least squares mean difference: -0.67; SE, 0.95; [95% CI: -2.54, 1.20]; P = .48; Cohen's d effect size: 0.07). Treatment-emergent adverse events occurred in 30.4% with pimavanserin and 40.3% with placebo.

In this study, pimavanserin was well tolerated, and although it demonstrated a similar treatment effect as in the prior phase 2 study favoring pimavanserin, treatment with pimavanserin vs placebo did not result in significant differences for primary or other endpoints.

This study aims to assess the therapeutic effects of intermittent theta burst stimulation (iTBS) targeting the bilateral dorsomedial prefrontal cortex (DMPFC) on negative symptoms in patients with schizophrenia, utilizing functional near-infrared spectroscopy for evaluation.

Thirty-five schizophrenia patients with negative symptoms and moderate to severe cognitive impairment were randomly assigned to a treatment group (n = 18) or a control group (n = 17). The treatment group received iTBS via bilateral DMPFC. Negative symptoms, cognitive function, emotional state, and social function were assessed using Positive and Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS), Montreal Cognitive Assessment (MoCA), Calgary Depression Scale for Schizophrenia (CDSS), and Social Dysfunction Screening Questionnaire (SDSS) scales at pretreatment, posttreatment, and follow-up at 4, 8, and 12 weeks. Brain activation in regions of interest (ROIs) was evaluated through verbal fluency tasks.

Prior to treatment there was no significant difference in the two groups. After 20 iTBS sessions, a significant difference was observed in SANS total score, its related subscales, PANSS total score, and PANSS-negative symptoms (all P < 0.05). The group-by-time interaction showed statistical significance, indicating improvements in negative symptoms and related dimensions over time, with therapeutic effects persisting for at least 8 weeks posttreatment. Prior to treatment, there were no significant differences in activation across all ROIs between the two groups. Posttreatment, the activation of right inferior frontal gyrus (t = 2.19, P = 0.036) and right frontal eye field (t = 2.14, P = 0.04) in the treatment group was significantly higher than in the control group.

iTBS stimulation of bilateral DMPFC demonstrates therapeutic effects in improving negative symptoms in schizophrenia patients, and this treatment approach has the potential to enhance activation within the prefrontal cortex.

Individuals diagnosed with schizophrenia present diverse degrees and types of cognitive impairment, leading to variations in responses to antipsychotic treatments. Understanding the underlying cognitive structures is crucial for assessing this heterogeneity. Utilizing latent profile analysis (LPA) enables the delineation of latent categories of cognitive function. Integrating this approach with a dimensional perspective allows for the exploration of the relationship between cognitive function and treatment response.

This study examined 647 patients from two distinct cohorts. Utilizing LPA within the discovery cohort (n = 333) and the replication cohort (n = 314), latent subtypes were identified categorically. The stability of cognitive structures was evaluated employing Latent Transition Analysis (LTA). The relationship between cognitive function and treatment response were investigated by comparing Positive and Negative Syndrome Scale (PANSS) reduction rates across diverse cognitive subtypes. Furthermore, dimensional insights were gained through correlation analyses between cognitive tests and PANSS reduction rates.

In terms of categorical, individuals diagnosed with schizophrenia can be categorized into three distinct subtypes: those 'without cognitive deficit', those 'with mild-moderate cognitive 'eficit', and those 'with moderate-severe cognitive deficit'. There are significant differences in PANSS reduction rates among patients belonging to these subtypes following antipsychotic treatment (p < 0.05). Furthermore, from a dimensional perspective, processing speed at baseline is positively correlated with PANSS score reduction rates at week 8/week 10 (p < 0.01).

Our findings have unveiled the latent subtypes of cognitive function in schizophrenia, illuminating the association between cognitive function and responses to antipsychotic treatment from both categorical and dimensional perspectives.

Schizophrenia is a complex psychiatric disorder characterized by positive, negative, and cognitive symptoms. KarXT, a novel combination of xanomeline and trospium, offers potential therapeutic benefits for schizophrenia treatment by targeting muscarinic receptors and avoiding dopamine receptor blockade. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of KarXT.

PubMed, Scopus, Web of Science, and Cochrane databases were systematically searched for relevant randomized controlled trials (RCTs) up to October 2024. Studies involving adult patients with schizophrenia treated with KarXT were included. Furthermore, the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was used to assess evidence quality, and the risk of bias was evaluated using the Cochrane Risk of Bias 2.0 tool.

Four studies with 690 participants were included. KarXT significantly reduced Positive and Negative Syndrome Scale (PANSS) total scores compared to placebo (mean difference (MD): -13.77, 95% confidence interval (CI) [-22.33 to -5.20], P-value = 0.002), with significant improvements in positive and negative subscale scores. It significantly increased the incidence of achieving ≥ 30% PANSS score reduction (risk ratio: 2.15, 95% CI [1.64 to 2.84], P < 0.00001). Moreover, KarXT demonstrated a favorable safety profile, with side effects such as nausea and constipation being mild and transient. Notably, it was not significantly associated with weight gain or extrapyramidal symptoms, which are common with traditional antipsychotics.

KarXT's distinct mechanism and tolerability highlight its potential to address unmet needs in schizophrenia treatment. Future studies should explore its long-term efficacy, delayed adverse effects, and comparative effectiveness against existing therapies.

Not applicable.

Negative symptoms in schizophrenia remain a challenge with limited therapeutic strategies. The novel compound RG7203 promotes reward learning via dopamine D1-dependent signaling and therefore holds promise, especially to improve the apathy dimension of negative symptoms. When tested as add-on to antipsychotic medication, apathy did not change significantly with RG7203 versus placebo. However, the response varied across patients, and a subset showed clinically relevant improvement of apathy. It remains unclear if these interindividual differences are related to neurobiological correlates.

Due to the predominant binding of RG7203 in the striatum, we investigated how apathy changes with RG7203 are related to changes in cortico-striatal connectivity by computing rank correlations (rs). In a post hoc exploratory analysis, we focused on cortico-striatal circuits that have been associated with apathy and previously showed connectivity alterations in schizophrenia. In a double-blind, 3-way randomized and counterbalanced crossover study, resting-state functional magnetic resonance imaging was acquired from 24 individuals with schizophrenia following a 3-week administration of placebo, 5 mg, or 15 mg of RG7203 as an add-on to antipsychotics.

We found that 5 mg or 15 mg of RG7203 did not lead to significant changes in striatal connectivity. However, changes in the apathy response across individuals were reflected by striatal connectivity changes. Apathy improvement with 5 mg and 15 mg RG7203 vs. placebo was associated with increased striatal connectivity to paracingulate (rs = - 0.58, p = 0.047 for both doses) and anterior cingulate regions (rs = - 0.56, p = 0.047 for both doses). Such associations were not observed for the negative symptom dimension of expressive deficits. We additionally observed that lower striatal connectivity to paracingulate and anterior cingulate regions during placebo was linked to greater apathy improvement during RG7203 treatment at both doses (rs = 0.61-0.79 and p = 0.0002-0.02 across regions and doses).

These findings suggest that striatal connectivity with the paracingulate gyrus and anterior cingulate cortex may be associated with apathy modulation under RG7203 treatment. Replication and further elaboration of these findings in larger clinical studies could help to advance biologically informed and personalized treatment options for negative symptoms.

NCT02824055, registered on ClinicalTrials.gov (2016-06-21).

Aerobic exercise (AE) and cognitive remediation (CR) have both shown promising effects on cognition in schizophrenia. However, the efficacy of combining these interventions has not been thoroughly evaluated. We conducted a randomized controlled trial to test the 3-month effects of AE, CR, and their combination on cognition and functioning in patients with schizophrenia. A total of 59 patients were randomized into three groups: AE alone (n = 19), CR alone (n = 19), or a combination of both (n = 21). The intervention consisted of a combination of individual and group AEs and a computer-assisted CR. The overall retention rate was 91.53 %. The primary outcome was the change in cognition from baseline, assessed using the Brief Assessment of Cognition in Schizophrenia (BACS). Significant improvements from baseline to post-treatment were observed in the combined AE and CR group compared to the AE alone group for verbal memory, executive function, and the composite score on the BACS. Similarly, greater improvements were found in the combined AE and CR group than in the CR group alone in verbal memory, working memory, attention, executive function, and the composite BACS score, with effect sizes ranging from moderate to large. No significant differences were found in functional level changes from baseline to post-treatment in the pairwise comparisons between groups, as assessed using the modified Global Assessment of Functioning for social functioning Scale. Our results indicate that patients with schizophrenia in the combined AE and CR group achieved greater cognitive improvement than those in the AE or CR alone group.

The amygdala is a small but critical multi-nucleus structure for emotion, cognition and neuropsychiatric disorders. Although genetic associations with amygdala volumetric traits have been investigated in sex-combined European populations, cross-ancestry and sex-stratified analyses are lacking. Here we conducted cross-ancestry and sex-stratified genome-wide association analyses for 21 amygdala volumetric traits in 6,923 Chinese and 48,634 European individuals. We identified 191 variant-trait associations (P < 2.38 × 10-9), including 47 new associations (12 new loci) in sex-combined univariate analyses and seven additional new loci in sex-combined and sex-stratified multivariate analyses. We identified 12 ancestry-specific and two sex-specific associations. The identified genetic variants include 16 fine-mapped causal variants and regulate amygdala and fetal brain gene expression. The variants were enriched for brain development and colocalized with mood, cognition and neuropsychiatric disorders. These results indicate that cross-ancestry and sex-stratified genetic association analyses may provide insight into the genetic architectures of amygdala and subnucleus volumes.

Schizophrenia (SCZ) is associated with abnormal neural activities and brain connectivity. Electroencephalography (EEG) microstate is a voltage topographical representation of temporary brain network activations. Most research on EEG microstates in SCZ has focused on differences between patients and healthy controls (HC). However, changes in EEG microstates among SCZ patients across various stages of physiological and cognitive development have not been thoroughly assessed. Consequently, we stratified patients with SCZ into four age-specific cohorts (20-29 years (brain maturation), 30-39 years (stabilization), 40-49 years (early aging), and 50-59 years (advanced aging)) to evaluate EEG microstate alterations. Additionally, we assessed changes in EEG microstates in first-episode psychosis (FEP) before and after an 8-week treatment period.

We acquired 19-channel resting-state EEG from 140 chronic SCZ patients, aged 20 to 59 years, as well as from 19 FEP and 20 healthy controls. FEP patients underwent an 8-week inpatient follow-up. After pre-processing, EEG data from different groups were subjected to microstate analysis, and the K-Means clustering algorithm was applied to classify the data into 4 microstates. Subsequently, templates of these microstates were used to fit EEG signals from each patient, and the collected microstate parameters were analyzed.

Patients with SCZ aged 20 to 29 years demonstrated an increased time coverage of microstate class D compared to other age cohorts. In individuals aged 30-39 years, the parameters of microstate class B-specifically time coverage and occurrence-exhibited significant reductions relative to those in the 40-49 and 50-59 years age groups. Compared to healthy controls, microstates class A parameters were significantly reduced in SCZ patients, while microstates class C parameters were prolonged; after 8 weeks of treatment, microstates class A parameters increased and microstates class C parameters decreased.

Alterations in microstate dynamics were observed among SCZ patients across developmental stages, suggesting potential changes in brain activity patterns. Changes in microstates A and C may serve as potential biomarkers for evaluating treatment efficacy, establishing a foundation for personalized therapeutic approaches.

Schizophrenia is a highly heterogeneous disease, and a high percentage of patients are at high risk of developing somatic comorbidities, which must be taken into account in disease management and treatment selection.

Antipsychotics are often associated with side effects that worsen the somatic comorbidities. Among the different options, cariprazine is generally safe and usually well tolerated in both acute and long-term treatment and is often a good choice when balancing clinical benefits and side effects. Given the lack of consensus on the priority of symptoms to treat and the reasons for switching therapy based on the balance between side effects and symptom resolution, twelve psychiatrists met for an expert meeting to discuss the most common and worrisome antipsychotic side effects leading to switching, the most important somatic comorbidities, and the best way to address specific symptoms in both the acute and maintenance phases of treatment in schizophrenia. Special attention was given to metabolic comorbidities, sexual dysfunction, and cardiovascular disease. This paper aims to examine the relationship between schizophrenia and specific somatic comorbidities, to discuss how the balance between efficacy and tolerability influences treatment choice in the acute and maintenance treatment of schizophrenia, and how these two variables may have different priorities at different stages of treatment.

The choice of treatment is based primarily on efficacy and tolerability. Cariprazine is beneficial in patients with positive and negative symptoms, and it has a side-effect profile with low rates of metabolic side effects, sedation, and sexual dysfunction.

The dorsolateral prefrontal cortex (DLPFC) - cerebellum circuit has been implicated in the pathogenesis of negative symptoms of schizophrenia (SZ). Both areas are considered separate targets for repetitive transcranial magnetic stimulation (rTMS) treatment, showing potential for improving negative symptoms. However, there is still a lack of research that targets both DLPFC and cerebellum simultaneously. In this study, we will explore the efficacy and safety of dual-target rTMS based on the DLPFC-cerebellum circuit in the treatment of negative symptoms in SZ.

The study is a multicenter randomized, double-blind, and sham-controlled trial. First-episode schizophrenia is treated with adjunctive 1 Hz rTMS to the right DLPFC and intermittent theta burst stimulation (iTBS) to the cerebellum delivered sequentially in 20 sessions (active group) or a sham condition (sham group) along with antipsychotics. Clinical symptoms are assessed using the Positive and Negative Symptom Scale (PANSS) at baseline (T0), at the middle of the TMS intervention (after 10 sessions, T1), at the end of the intervention (after 20 sessions, T2), and at a 4-week follow-up after the intervention concludes (T3). Subjects will undergo magnetic resonance imaging (MRI) scans twice: once at baseline (T0) and again at the end of TMS intervention (T2). Comparisons of improvements in negative symptoms are conducted between the active and sham groups. Alterations in functional connectivity (FC) are also compared between both groups. Pearson or Spearman correlation analysis is performed to estimate the relationship between FC alteration and clinical symptom remission (PANSS negative subscale reduction scores and response rates, etc) depending on whether the data follows a normal distribution. In addition, potential neuroimaging biomarkers based on MRI associated with TMS treatment will be explored.

Positive results from this double-blind, sham-controlled, randomized study may optimize the TMS treatment strategy for SZ, particularly in managing negative symptoms. Clinicians can select TMS with increased confidence as a safe adjunctive treatment option. Furthermore, the findings of this trial may offer preliminary insights into the potential neuroimaging therapeutic mechanisms of TMS interventions targeting the prefrontal-cerebellar circuit.Trial registration: ClinicalTrials.govNCT04853485Primary sponsor: Jijun WANG (J. Wang), Principal Investigator: jijunwang27@163.com.

The negative symptoms of schizophrenia include diminished emotional expression, avolition, alogia, anhedonia, and asociality, and due to their low responsiveness to available treatments, are a primary driver of functional disability in schizophrenia. This narrative review has the aim of providing a comprehensive overview of the current research developments in the treatment of negative symptoms in schizophrenia, and begins by introducing the concepts of primary, secondary, prominent, predominant, and broadly defined negative symptoms. We then compare and contrast commonly used research assessment scales for negative symptoms and review the evidence for the specific utility of widely available off-label and investigational treatments that have been studied for negative symptoms. Mechanism of action/putative treatments included are antipsychotics (D2R antagonists), N-methyl-D-aspartate receptor (NMDAR) and other glutamatergic modulators, serotonin receptor (5-HTR) modulators, anti-inflammatory agents, antidepressants, pro-dopaminergic modulators (non-D2R antagonists), acetylcholine modulators, oxytocin, and phosphodiesterase (PDE) inhibitors. With the caveat that no compounds are definitively proven as gold-standard treatments for broadly defined negative symptoms, the evidence base supports several potentially beneficial off-label and investigational medications for treating negative symptoms in schizophrenia, such as monotherapy with cariprazine, olanzapine, clozapine, and amisulpride, or adjunctive use of memantine, setrons such as ondansetron, minocycline, and antidepressants. These medications are widely available worldwide, generally tolerable and could be considered for an off-label, time-limited trial for a predesignated period of time, after which a decision to switch or stay can be made based on clinical response. Among investigational medications, NMDAR agonists, muscarinic agonists, and LB-102 remain under study. Suggestions for future research include reducing placebo effects by designing studies with a smaller number of high-quality study sites, potentially increasing the use of more precise rating scales for negative symptoms, and focused studies in people with predominant negative symptoms.

As a central component of schizophrenia psychopathology, negative symptoms result in detrimental effects on long-term functional prognosis. However, the neurobiological mechanism underlying negative symptoms remains poorly understood, which limits the development of novel treatment interventions. This study aimed to identify the specific neural fingerprints of negative symptoms in schizophrenia.

Based on resting-state functional connectivity data obtained in a large sample (n = 132) of first-episode drug-naïve schizophrenia patients (DN-FES), connectome-based predictive modeling (CPM) with cross-validation was applied to identify functional networks that predict the severity of negative symptoms. The generalizability of identified networks was then validated in an independent sample of n = 40 DN-FES.

A connectivity pattern significantly driving the prediction of negative symptoms (ρ = 0.28, MSE = 81.04, P = 0.012) was identified within and between networks implicated in motivation (medial frontal, subcortical, sensorimotor), cognition (default mode, frontoparietal, medial frontal) and error processing (medial frontal and cerebellum). The identified networks also predicted negative symptoms in the independent validation sample (ρ = 0.37, P = 0.018). Importantly, the predictive model was symptom-specific and robust considering the potential effects of demographic characteristics and validation strategies.

Our study discovers and validates a comprehensive network model as the unique neural substrates of negative symptoms in schizophrenia, which provides a novel and comprehensive perspective to the development of target treatment strategies for negative symptoms.

Few studies have examined the long-term outcomes of first-episode psychosis (FEP) among patients beyond symptomatic and functional remission. This study aimed to broaden the scope of outcome indicators by examining the relationships between 12 outcomes of FEP patients at 20.9 years after their initial diagnosis.

At follow-up, 220 out of 550 original patients underwent a new assessment. Twelve outcomes were assessed via semistructured interviews and complementary scales: symptom severity, functional impairment, personal recovery, social disadvantage, physical health, number of suicide attempts, number of episodes, current drug use, dose-years of antipsychotics (DYAps), cognitive impairment, motor abnormalities, and DSM-5 final diagnosis. The relationships between these outcome measures were investigated using Spearman's correlation analysis and exploratory factor analysis, while the specific connections between outcomes were ascertained using network analysis.

The outcomes were significantly correlated; specifically, symptom severity, functioning, and personal recovery showed the strongest correlations. Exploratory factor analysis of the 12 outcomes revealed two factors, with 11 of the 12 outcomes loading on the first factor. Network analysis revealed that symptom severity, functioning, social disadvantage, diagnosis, cognitive impairment, DYAps, and number of episodes were the most interconnected outcomes.

Network analysis provided new insights into the heterogeneity between outcomes among patients with FEP. By considering outcomes beyond symptom severity, the rich net of interconnections elucidated herein can facilitate the development of interventions that target potentially modifiable outcomes and generalize their impact on the most interconnected outcomes.

This study compares the clinical features of Treatment-Resistant Schizophrenia (TRS) and Non-Treatment-Resistant Schizophrenia (NTRS) using network analysis.

We recruited 511 patients, dividing them into TRS (N = 269) and NTRS (N = 242) groups. Eight scales were used: Positive and Negative Syndrome Scale (PANSS), Positive Symptom Assessment Scale (SAPS), Scale for Assessment of Negative Symptoms (SANS), Simpson-Angus Scale (SAS), Abnormal Involuntary Movements Scale (AIMS), Barnes Akathisia Rating Scale (BARS), Calgary Schizophrenia Depression Scale (CDSS), and Global Assessment of Functioning Scale (GAF). Demographic and clinical data were analyzed using T-tests and Chi-square tests. Network analysis was then applied to compare clinical features.

Significant differences were found in the overall architectures (S = 1.396, p < 0.002) and edge weights (M = 0.289, p < 0.009) of TRS and NTRS networks. Nine edges (p < 0.05) and five nodes (p < 0.01) differed, indicating a correlation between clinical symptoms of the two groups. TRS core symptoms were linked to social functions through both positive (SAPS) and negative symptoms (SANS), while NTRS core symptoms were related to general psychopathological symptoms (PANSS-G).

For TRS, it is essential to address both negative and positive symptoms, focusing on the impact of negative symptoms on functioning. Additionally, managing medication side effects is crucial to avoid worsening negative symptoms.

Synaptic dysfunction is involved in schizophrenia pathophysiology. However, whether in vivo synaptic density is reduced in early stages of psychosis, including its high-risk states, remains unclear.

To investigate whether synaptic density (synaptic vesicle glycoprotein 2A [SV2A] binding potential) is reduced in first-episode psychosis (FEP) and in clinical high risk (CHR) and investigate the effect of cannabis use on synaptic density and examine its relationship with psychotic symptoms and gray matter microstructure across groups.

This cross-sectional study was performed in a tertiary care psychiatric hospital from July 2021 to October 2023. Participants were patients with antipsychotic-free or minimally exposed FEP or CHR and healthy controls with a clean urine drug screen (except cannabis).

Synaptic density was quantified with dynamic 90-minute [18F]SynVesT-1 positron emission tomography (PET) scans across prioritized brain regions of interest (ROIs) delineated in individual magnetic resonance images (MRIs). Cannabis use was confirmed with urine drug screens. Gray matter microstructure was assessed using diffusion-weighted MRI to estimate neurite density.

A total of 49 participants were included, including 16 patients with FEP (mean [SD] age, 26.1 [4.6] years; 9 males and 7 females), 17 patients at CHR (mean [SD] age, 21.2 [3.5] years; 8 males and 9 females), and 16 healthy controls (mean [SD] age, 23.4 [3.6] years; 7 males and 9 females). Synaptic density was significantly different between groups (F2,273 = 4.02, P = .02, Cohen F = 0.17; ROI: F5,273 = 360.18, P < .01, Cohen F = 2.55) with a group × ROI interaction (F10,273 = 2.67, P < .01, Cohen F = 0.32). Synaptic density was lower in cannabis users (F1,272 = 5.31, P = .02, Cohen F = 0.14). Lower synaptic density across groups was associated with more negative symptoms (Positive and Negative Syndrome Scale negative scores: F1,81 = 4.31, P = .04, Cohen F = 0.23; Scale of Psychosis-Risk Symptoms negative scores: F1,90 = 4.12, P = .04, Cohen F = 0.21). SV2A binding potential was significantly associated with neurite density index (F1,138 = 6.76, P = .01, Cohen F = 0.22).

This study found that synaptic density reductions were present during the early stages of psychosis and its risk states and associated with negative symptoms. The implications of SV2A for negative symptoms in psychosis and CHR warrant further investigation. Future studies should investigate the impact of cannabis use on synaptic density in CHR longitudinally.

Experiential negative symptoms (NS) are determinants of disability in schizophrenia (SCZ). Xanomeline/Trospium Chloride (X/T), an M1/M4 muscarinic receptor agonist, is an approved monotherapy for treatment of schizophrenia, including NS. We used remote ecological momentary assessments (EMA) to track changes in indicators of NS during 12 months of outpatient treatment with X/T.

After discontinuing previous medications, 566 outpatients with SCZ received open-label X/T monotherapy for up to 12 months. Participants completed 3 EMA surveys 7 days a week, one week a month. Surveys queried whether participants were home vs. away and alone vs with someone, as well as productive and unproductive activities, and moods. Hierarchical linear modeling (HLM) examined temporal changes and the relationships between the indicators of NS.

500 participants answered one or more EMA surveys and 350 met 33 % adherence criteria, answering a total of 40,464 surveys, with overall adherence among these participants at 66 %. During treatment with X/T, there were significant decreases in surveys at home (p < .001), alone (p < .001), and engaging in unproductive activities (p < .001). There were significant increases in productive activities both home (p < .001) and away (p < .001) and in positive affect (PA) (p < .001). Improvements in PA converged with reduced unproductive activities, particularly when others were present (p < .001).

Behavioral indicators of NS improved early and were sustained with X/T treatment. Improvements were multidimensional, shifting toward more time with others, away from home, and engaged in productive activities. These improvements were associated with increases in PA, consistent with previous EMA studies of NS.

Promoting positive mental health is crucial for maintaining a healthy balance of mental well-being, both for individuals with and without mental health conditions, including schizophrenia.

To map interventions that promote positive mental health in individuals with schizophrenia.

We conducted a scoping review following Joanna Briggs Institute recommendations. Searches were performed on Scopus, MEDLINE and CINAHL Complete (via EBSCOhost), and RCAAP for grey literature. Papers that met the following criteria were included: published from September 1999 to May 2023; involving only individuals diagnosed with schizophrenia; focused on interventions that promote positive mental health; presenting interventions with defined objectives and duration; designed for individuals or groups.

We identified 1111 potentially relevant records, which were screened by 2 independent researchers. 26 studies, published between 2004 and 2023 were found eligible. Most of the identified interventions were implemented in community-based settings (n = 22), in group formats (n = 20), with a total duration between 4 and 12 weeks (n = 20), session duration about 45-60 min (n = 13) and without follow up (n = 17). A significant number of interventions focused on improving interpersonal relationship capacity (n = 15) and personal satisfaction (n = 13). 9 interventions focused on enhancing autonomy, 3 on promoting self-control, 2 on problem-solving/self-actualization and 1 on promoting pro-social attitude.

This scoping review can contribute to improving the quality of care provided and optimizing health outcomes, enhancing the promotion of community health through increased knowledge in the field of positive mental health.

Therapeutic ketosis could target the potential bio-energetic pathophysiology of schizophrenia. Ideally, novel treatments also target the possible inflammatory aspects of schizophrenia. Adult mice (n = 30) were treated with ketone ester (KE) or vehicle for 3 days, next LPS- or PBS-injected. Brains were collected the next day. KE significantly attenuated the increased transcription of the pro-inflammatory cytokines Tnf-a, Il-6 and Il-1b, without affecting anti-inflammatory/immunomodulatory cytokines (Il-4, Il-10, Il-11) in whole brain. KE potently dampened neuro-inflammation in this acute inflammation mouse model. Ketone therapy could simultaneously target two possible pathophysiological pathways in schizophrenia. We encourage more research into the immunometabolic potential of therapeutic ketosis in schizophrenia.

The assessment of negative symptoms in schizophrenia has advanced since the 2006 NIMH-MATRICS Consensus Statement, leading to the development of second-generation rating scales like the Brief Negative Symptom Scale and the Clinical Assessment Interview for Negative Symptoms. These scales address the limitations of first-generation tools, such as the inclusion of aspects that are not negative symptoms and the lack of assessment of the subject's internal experience. However, psychometric validation of these scales is still in progress, and they are not yet recommended by regulatory agencies, thus limiting their use in clinical trials and settings. Complementing these traditional methods, remote digital phenotyping offers a novel approach by leveraging smartphones and wearable technology to capture real-time, high-resolution clinical data. Despite the potential to overcome traditional assessment barriers, challenges remain in aligning these digital measures with clinical ratings and ensuring data security. Equally important is patient acceptance, as the success of remote digital phenotyping relies on the willingness of patients to use these technologies. This review provides a critical overview of both second-generation scales and remote digital phenotyping for assessing negative symptoms, highlighting future research needs.

Patients with early psychosis (EP) (within 3 years after psychosis onset) show significant variability, which makes predicting outcomes challenging. Currently, little evidence exists for stable relationships between neural microstructural properties and symptom profiles across EP diagnoses, which limits the development of early interventions.

A data-driven approach, partial least squares correlation, was used across 2 independent datasets to examine multivariate relationships between white matter properties and symptomatology and to identify stable and generalizable signatures in EP. The primary cohort included patients with EP from the Human Connectome Project for Early Psychosis (n = 124). The replication cohort included patients with EP from the Feinstein Institute for Medical Research (n = 78) as part of the MEND (Multimodal Evaluation of Neural Disorders) Project. Both samples included individuals with schizophrenia, schizoaffective disorder, and psychotic mood disorders.

In both cohorts, a significant latent component corresponded to a symptom profile that combined negative symptoms, primarily diminished expression, with specific somatic symptoms. Both latent components captured comprehensive features of white matter disruption, primarily a combination of subcortical and frontal association fibers. Strikingly, the partial least squares model trained on the primary cohort accurately predicted microstructural features and symptoms in the replication cohort. Findings were not driven by diagnosis, medication, or substance use.

This data-driven transdiagnostic approach revealed a stable and replicable neurobiological signature of microstructural white matter alterations in EP across diagnoses and datasets, showing strong covariance of these alterations with a unique profile of negative and somatic symptoms. These findings suggest the clinical utility of applying data-driven approaches to reveal symptom domains that share neurobiological underpinnings.

Among individuals living with psychotic disorders, social impairment is common, debilitating, and challenging to treat. While the roots of this impairment are undoubtedly complex, converging lines of evidence suggest that social motivation and pleasure (MAP) deficits play a central role. Yet most neuroimaging studies have focused on monetary rewards, precluding decisive inferences.

Here we leveraged parallel social and monetary incentive delay functional magnetic resonance imaging paradigms to test whether blunted reactivity to social incentives in the ventral striatum-a key component of the distributed neural circuit mediating appetitive motivation and hedonic pleasure-is associated with more severe MAP symptoms in a transdiagnostic adult sample enriched for psychosis. To maximize ecological validity and translational relevance, we capitalized on naturalistic audiovisual clips of an established social partner expressing positive feedback.

Although both paradigms robustly engaged the ventral striatum, only reactivity to social incentives was associated with clinician-rated MAP deficits. This association remained significant when controlling for other symptoms, binary diagnostic status, or striatal reactivity to monetary incentives. Follow-up analyses suggested that this association predominantly reflects diminished activation during the presentation of social reward.

These observations provide a neurobiologically grounded framework for conceptualizing the social-anhedonia symptoms and social impairments that characterize many individuals living with psychotic disorders and underscore the need to develop targeted intervention strategies.

The heterogeneity of cognitive impairments in schizophrenia has been widely observed. However, reliable cognitive boundaries to differentiate the subgroups remain elusive. The key challenge for cognitive subtyping is applying an integrated and standardized cognitive assessment and understanding the subgroup-specific neurobiological mechanisms. The present study endeavors to explore cognitive subgroups and identify their morphological features.

A total of 920 schizophrenia patients and 169 healthy controls were recruited. MATRICS Consensus Cognitive Battery was applied to assess cognitive performance and recognize cognitive subgroups through latent profile and latent transition analysis. Cortical thickness and gray matter volume were employed for the morphological features across subgroups.

Four reproducible cognitive subgroups were identified, including multidomain-intact, executive-preserved, executive-deteriorated, and multidomain-deteriorated subgroup. After 12 weeks of follow-up, the cognitive characteristics of three out of the four subgroups kept stability, except for multidomain-deteriorated subgroup in which 48.8% of patients with improved cognition transited into the executive-deteriorated subgroup. Across subgroups, significant gradient features of brain structure were exhibited in fronto-temporal regions, hippocampus, and insula. Compared to healthy controls, multidomain-intact subgroup showed the most intact cognition and morphology, and multidomain-deteriorated subgroup with youngest age showed morphological decline in extensive regions. The remaining two subgroups showed intermediate cognitive performance, but could be distinguished by executive function and morphological differences in posterior cingulate cortex.

Our study provides novel insights into the heterogeneity of cognitive impairments in schizophrenia and the morphological features from cross-sectional and longitudinal levels, which could advance our understanding of complex cognition-morphology relationships and guide personalized interventions.

The present study aimed to investigate the causal relationships among cognitive impairment, psychopathology, and real-life functioning in a large sample of people with schizophrenia, using a data-driven causal discovery procedure based on partial ancestral graphs (PAGs). This method may provide additional insights for the identification of potential therapeutic targets to promote recovery in people with chronic schizophrenia. State-of-the-art instruments were used to assess the study variables. Two PAGs were generated at baseline and after 4 years of follow-up to model the nature of the causal relationships linking psychopathology, cognition, and functioning. The study sample was composed of more than 600 clinically stable patients with schizophrenia at two time points. The PAGs model indicated that working memory impairment is the first ancestor of the causal links, influencing all the other neurocognitive domains, social cognition, and functional capacity, which in turn affects everyday life functioning. From this domain of functioning a causal link is directed to disorganization and positive symptoms, and another to work skills and interpersonal relationships domains; the latter had a direct link to asociality and the other domains of negative symptoms. The structure of the PAGs did not differ significantly between baseline and follow-up, indicating the stability of the causal relationship model investigated cross-sectionally at both time points. The role of working memory impairment in the pathways to functional outcomes in schizophrenia highlights the importance of implementing integrated pharmacological and cognitive remediation interventions targeting neurocognition. The impact of everyday life and interpersonal functioning on the clinical presentation of schizophrenia suggests that integrated and personalized treatments, promoting relevant skills to improve these functional outcomes, may have a beneficial impact on clinical outcomes.

Mental health encompasses the ability to cope with important stresses of life and to realize one's abilities in the community, and the COVID-19 pandemic represented a very stressful event for people with mental illnesses. Our aim was to assess mental well-being in people living with different mental disorders, comparing results obtained in 2016 with those observed after the COVID-19 pandemic. Ninety-six participants were assessed using the Mental Health Continuum Short Form and classified as "flourishing," "moderately mentally healthy," and "languishing." Overall, a significant increase in the prevalence of "flourishing" and "moderately mentally healthy" subjects and a reduction of "languishing" subjects ( p = 0.003) were observed. However, a significant improvement in well-being ( p = 0.005) was observed only in the schizophrenia spectrum disorder group. Moreover, only subjects that never contracted SARS-CoV-2 showed a significant ( p = 0.019) increase in positive well-being states. Lockdowns may have led caregivers to spend more time with the participants, also increasing treatment adherence, resulting in an improvement of overall well-being in several participants.

Antipsychotic medications are a vast class of drugs used for the treatment of psychotic disorders such as schizophrenia. Although numerous compounds have been developed since their introduction in the 1950s, several patients do not adequately respond to current treatments, or they develop adverse reactions that cause treatment discontinuation. Moreover, in the past few decades, discoveries in the pathophysiology of psychotic disorders have opened the way for experimenting with novel compounds that have alternative mechanisms of action, with some of them showing promising results in early trials. The scope of this review was to summarize the novel antipsychotics developed, their current experimental status, and their mechanisms of action. In particular, we analyzed the main classes of investigational antipsychotics, such as monoamine, glutamate, acetylcholine, cannabinoid receptor modulators, enzyme inhibitors, ion channel modulators, and mixed receptor modulators. In addition, the safety profiles and adverse effects of these drugs were carefully evaluated, considering the relevance of these aspects for patients' drug adherence and quality of life, especially in the long-term treatment. Lastly, we tried to understand which compounds have greater potential to be approved by the principal drug regulatory agencies in the next years and if they could be used for diseases other than psychotic disorders.

To explore the efficacy of theta burst stimulation (TBS) on the negative symptoms in patients with chronic schizophrenia, and to investigate the alterations of local brain activity using functional near-infrared spectroscopy (fNIRS).

100 patients with chronic schizophrenia were enrolled and divided into the real group (50 subjects) and sham group (50 subjects). The real group was given real stimulation of TBS for 4 weeks, and the sham group was sham-stimulated with the same site. The Positive and Negative Symptom Scale (PANSS) and the Scale for Assessment of Negative Symptoms (SANS) were used to assess the clinical symptoms. fNIRS was used to detect the amplitude of low frequency fluctuation (ALFF) of cortical hemoglobin before and after TBS. Repeated analysis of variance (ANOVA) was used to compare the changes in clinical features between the two groups. Correlation analysis was used to explore the associations between altered ALFF and clinical features.

Repeated ANOVA revealed that the interaction effect of group∗time showed significant influence on the scores of PANSS-total, PANSS-negative, and SANS in the two groups of patients. Test of within-subjects effects showed that significant reductions in scores of PANSS-total, PANSS-negative, and SANS were found between the real group and sham group after TBS, as well as in the real group before and after TBS. fNIRS revealed that the normalized ALFF (zALFF) of deoxyhemoglobin in the left dorsolateral prefrontal cortex was decreased in the real group after TBS. Furthermore, the zALFF of oxyhemoglobin was increased in the right and left frontal pole regions, and decreased in the right superior temporal gyrus in the real group compared to the sham group after TBS. Correlation analysis showed that the alterations of zALFF in frontal regions after treatment were associated with the improvement of negative symptoms in chronic schizophrenia patients.

Short-term TBS is effective in the improvement of negative symptoms of chronic schizophrenia. fNIRS could reveal the changes in brain activity after TBS treatment, providing an effective technique for exploring the efficacy of TBS in schizophrenia.

Negative symptoms in schizophrenia spectrum disorders are related to impaired social functioning and lower quality of life, making accurate assessment important. To date, most tools for assessing negative symptoms are observational, which can be influenced by the raters' experience and opinion. Self-rating scales, like the Self-Evaluation of Negative Symptoms (SNS), could complement observer ratings by adding information from the patient's perspective. Here, we aim to evaluate the psychometric properties of the Dutch translation of the SNS and the relationship between the SNS and functional outcomes.

The SNS was added to the Pharmacotherapy Monitoring Outcome Survey (PHAMOUS)-protocol for adults with a DSM-5 classification of a disorder in the psychosis spectrum. Internal consistency was assessed by Cronbach's alpha. Confirmatory factor analysis (CFA) was used to evaluate the construct validity of the five subscales of the SNS. Correlational analyses were performed between the SNS and the Positive and Negative Syndrome Scale (PANSS), the Health of Nation Outcomes Scales (HoNOS), the Global Assessment of Functioning (GAF), Functional Remission tool (FR) and the Manchester Short Assessment of Quality of Life (ManSA).

A total of 247 patients participated in this study. Internal consistency was good (α = 0.87). CFA confirmed the five-factor structure of the SNS. The SNS was significantly correlated (all p < 0.001) with the PANSS positive (r = 0.31), PANSS negative (r = 0.33), HoNOS (r = 0.37), FR (r = 0.27) and the ManSA (r = -0.40).

The Dutch SNS shows good psychometric properties and is related to functional outcomes and quality of life. The SNS can be valuable in complementing current observational-based instruments, and future research may investigate whether the SNS can be used as a standalone measurement tool for the assessment of negative symptoms.

Studies have shown associations between polygenic risk scores for educational attainment (PRSEA), cognitive reserve (CR), cognition, negative symptoms (NS), and psychosocial functioning in first-episode psychosis (FEP). However, their specific interactions remain unclear. This study aimed to investigate the mediating roles of CR, cognition, and NS in the relationship between PRSEA and psychosocial functioning one year after a FEP. Additionally, we sought to explore the impact of two NS subtypes on this relationship: diminished Expression (EXP-NS) and Motivation and Pleasure (MAP-NS).

A total of 138 FEP participants, predominantly male (70%), with a mean age of 24.77 years (SD = 5.29), underwent genetic, clinical, and cognitive assessments two months after study enrollment. Functioning evaluation followed at one-year follow-up. To investigate the mediating role of CR, cognition, and NS in the relationship between PRSEA and functioning, a serial mediation model was employed. Two further mediation models were tested to explore the differential impact of EXP-NS and MAP-NS. Mediation analysis was performed using the PROCESS macro version 4.1 within SPSS version 26.

The serial mediation model revealed a causal chain for PRSEA > CR > cognition > NS > Functioning (β = -3.08, 95%CI [-5.73, -0.43], p = 0.023). When differentiating by type of NS, only EXP-NS were significantly associated in the casual chain (β = -0.17, 95% CI [-0.39, -0.01], p < 0.05).

CR, cognition and NS -specifically EXP-NS- mediate the association between PRSEA and psychosocial functioning at one-year follow-up in FEP patients. These results highlight the potential for personalized interventions based on genetic predisposition.

Negative symptoms of schizophrenia are correlated with reduction of normal function and lower quality of life. They were newly defined by the NIMH-MATRICS Consensus in 2005, dividing the rating tools to assess them into first-generation scales, developed before the Consensus, and second-generation scales, based on the recently introduced definitions.

The COnsensus-based Standards for the selection of health Measurement Instrument (COSMIN) guidelines for systematic reviews were used to evaluate the quality of psychometric data of the first-generation scales that cover the 5 negative symptom domains of the NIMHS Consensus: the Scale for the Assessment of Negative Symptoms (SANS), the High Royds Evaluation of Negativity Scale (HEN), and the Negative Symptom Assessment-16 (NSA-16).

The search strategy resulted in the inclusion of a total of 13 articles, 7 for the SANS, 4 for the NSA-16, and 2 for the HEN. For the SANS and the NSA-16, the overall results of the scales' measurement properties are mostly insufficient or indeterminate. The quality of evidence for the HEN is poor, due to a small number of validation studies/included patients.

After applying the COSMIN guidelines, we do not recommend the usage of these first-generation scales to rate negative symptoms. At the minimum they require further validation.

Negative symptoms can be an integral part of schizophrenia spectrum pathology and can be secondary to other psychotic symptoms or caused by antipsychotic medication. As antipsychotic drugs differ in their affinity to dopamine receptors and some antipsychotics have partial agonistic effects, antipsychotic drugs are expected to vary in their ability to cause negative symptoms. The association between negative symptoms and antipsychotic medication divided into partial agonists, or antagonists with high or low D2 affinity was assessed in 310 remitted first episode psychosis (FEP) patients. Severity of negative symptoms was assessed with the Comprehensive Assessment of Symptoms and History, and the Positive and Negative Syndrome Scale. Linear regression analyses were performed while controlling for differences in clinical and sociodemographic characteristics between the groups using inverse probability of treatment weighting. Patients using partial agonists (n = 78) showed fewer negative symptoms compared to those using high affinity antagonists (n = 84). Patients using partial agonists displayed less severe negative symptoms compared to those using low affinity antagonists (n = 148) at a trend level (p = 0.051). Negative symptom severity was higher in patients who had higher antipsychotic doses. In remitted FEP patients, we observed that the use of antipsychotic medication classified as partial agonists was associated with lower severity of negative symptoms, while the use of antagonists with high D2 affinity was associated with more severe negative symptoms.

This overview of systematic reviews with meta-analysis aimed to summarize the effects of exercise, regular physical activity, and mind-body exercises on negative symptoms, depression symptoms, and quality of life in schizophrenia spectrum and other psychotic disorders.

The CINAHL, Embase, PubMed, SPORTDiscus, and the Cochrane Library databases were searched up to November 10, 2023. AMSTAR 2 was used and the overlap between reviews was calculated.

Eighteen reviews were included. No reviews meta-analyzed regular physical activity. Aerobic exercise may be more effective than yoga, treatment-as-usual, or multiple controls for reducing negative symptoms. Tai chi may be more effective than multiple controls for decreasing negative symptoms. Aerobic exercise or multimodal exercise programs may be more effective than multiple controls for reducing depression symptoms. Yoga may be more effective than waitlist for decreasing depression symptoms. Aerobic exercise may be more effective than multiple controls for improving quality of life. Yoga may be more effective than treatment-as-usual for improving quality of life. The rest of the meta-analyses found no differences between groups or combined different types of interventions in their meta-analyses.

Despite these results, important methodological concerns were detected that precluded us from making sound clinical recommendations.

https://doi.org/10.17605/OSF.IO/7V5QZ.

Treatment resistance (TR) in schizophrenia may be defined by the persistence of positive and/or negative symptoms despite adequate treatment. Whilst previous investigations have focused on positive symptoms, negative symptoms are highly prevalent, impactful, and difficult to treat. In the current study we aimed to develop easily employable prediction models to predict TR in positive and negative symptom domains from first episode psychosis (FEP).

Longitudinal cohort data from 1027 individuals with FEP was utilised. Using a robust definition of TR, n = 51 (4.97 %) participants were treatment resistant in the positive domain and n = 56 (5.46 %) treatment resistant in the negative domain 12 months after first presentation. 20 predictor variables, selected by existing evidence and availability in clinical practice, were entered into two LASSO regression models. We estimated the models using repeated nested cross-validation (NCV) and assessed performance using discrimination and calibration measures.

The prediction model for TR in the positive domain showed good discrimination (AUC = 0.72). Twelve predictor variables (male gender, cannabis use, age, positive symptom severity, depression and academic and social functioning) were retained by each outer fold of the NCV procedure, indicating importance in prediction of the outcome. However, our negative domain model failed to discriminate those with and without TR, with results only just over chance (AUC = 0.56).

Treatment resistance of positive symptoms can be accurately predicted from FEP using routinely collected baseline data, however prediction of negative domain-TR remains a challenge. Detailed negative symptom domains, clinical data, and biomarkers should be considered in future longitudinal studies.