Schizophrenia (SCZ) represents a considerable health concern, not only due to its impact on cognitive and psychiatric domains, but also because of its association with metabolic abnormalities. Individuals with SCZ face an increased risk of developing metabolic syndrome (MS), which contributes to the increased cardiovascular burden and reduced life expectancy observed in this population. Metabolic alterations are associated with both the SCZ condition itself and extrinsic factors, particularly the use of antipsychotic medications. Additionally, the link between SCZ and MS seems to be guided by distinct genetic parameters. The present narrative review summarizes the relationship between SCZ and MS and emphasizes the various therapeutic approaches for managing its components in patients with these conditions. Recommended therapeutic approaches include lifestyle modifications as the primary strategy, with a focus on behavioral lifestyle programs, addressing dietary patterns and physical activity. Pharmacological interventions include administering common antidiabetic medications and the selection of less metabolically harmful antipsychotics. Alternative interventions with limited clinical application are also discussed. Ultimately, a personalized therapeutic approach encompassing both the psychological and metabolic aspects is essential for the effective management of MS in patients with SCZ.

Varying combinations of genetic and environmental risk factors are thought to underpin phenotypic heterogeneity between individuals in psychiatric conditions such as schizophrenia. While epigenome-wide association studies in schizophrenia have identified extensive alteration of mean DNA methylation levels, less is known about the location and impact of DNA methylation variance, which could contribute to phenotypic and treatment response heterogeneity. To explore this question, we conducted the largest meta-analysis of blood DNA methylation variance in schizophrenia to date, leveraging three cohorts comprising 1036 individuals with schizophrenia and 954 non-psychiatric controls. Surprisingly, only a small proportion (0.1%) of the 213 variably methylated positions (VMPs) associated with schizophrenia (Benjamini-Hochberg FDR < 0.05) were shared with differentially methylated positions (DMPs; sites with mean changes between cases and controls). These blood-derived VMPs were found to be overrepresented in genes previously associated with schizophrenia and amongst brain-enriched genes, with evidence of concordant changes at VMPs in the cerebellum, hippocampus, prefrontal cortex, or striatum. Epigenetic covariance was also observed with respect to clinically significant metrics including age of onset, cognitive deficits, and symptom severity. We also uncovered a significant VMP in individuals with first-episode psychosis (n = 644) from additional cohorts and a non-psychiatric comparison group (n = 633). Collectively, these findings suggest schizophrenia is associated with significant changes in DNA methylation variance, which may contribute to individual-to-individual heterogeneity.

Serious mental disorders such as schizophrenia and major depression are associated with considerable morbidity and mortality, resulting in much shorter life expectancies in those affected. The discovery of antipsychotic medications ushered in improved health outcomes for people with serious mental disorders but also brought about increased morbidity due to their metabolic side effects, including obesity and diabetes mellitus. Antidepressant medications have a more favorable metabolic side effect profile, but some can still cause weight gain and hyperglycemia. In this narrative review, we discuss antipsychotic and antidepressant medications' mechanisms of action, their respective effectiveness in treating psychosis and depression, and their metabolic side effects. In addition, we present therapeutic strategies for minimizing cardiometabolic health risks in patients treated with these medications by applying a comprehensive, biopsychosocial approach.

We examined the acute effects of intranasal insulin on cognitive function and brain glutathione (GSH), a central factor in resistance to oxidative stress, in both participants with early psychosis and healthy control (HC) participants.

Twenty-one patients with early-stage psychotic disorders and 18 HC participants underwent magnetic resonance spectroscopy (MRS) scans and cognitive assessments before and after administration of intranasal insulin 40 IU. We conducted proton MRS (1H-MRS) in the prefrontal cortex at 4T to measure GSH and glutamate metabolites. We assessed cognition using the Brief Assessment of Cognition in Schizophrenia symbol coding, digit sequencing, and verbal fluency tasks, in addition to the Stroop task.

The mean (SD) age of participants was 25.7 (4.6) years; 51.3% were female. There were no significant group differences at baseline in age, sex, body mass index, homeostatic model assessment of insulin resistance (HOMA-IR), or cognition. Patients had higher baseline GSH (p < .001) and glutamate (p = .007). After insulin administration, GSH increased in HC participants (mean change, 0.15; 95% CI 0.03 to 0.26; p = .015), but not in patients. Symbol coding improved in both patients (0.74; 95% CI 0.37 to 1.11; p < .001) and HC participants (0.83; 95% CI 0.58 to 1.09; p < .001), and verbal fluency improved in HC participants (0.43; 95% CI 0.14 to 0.72; p = .006). Lower baseline HOMA-IR was associated with greater change in GSH (coefficient -0.22; 95% CI -0.40 to -0.04; p = .017).

Intranasal insulin increased brain GSH in HC participants, but not in patients with early psychotic disorders. These novel findings demonstrate that intranasal insulin enhances antioxidant capacity and resilience to oxidative stress in HC individuals in contrast to an absent antioxidant response in those with early psychotic disorders.

There is an urgent need for mechanistically novel and more efficacious treatments for schizophrenia, especially those targeting negative and cognitive symptoms with a more favorable side-effect profile. Drug repurposing-the process of identifying new therapeutic uses for already approved compounds-offers a promising approach to overcoming the lengthy, costly, and high-risk process of traditional CNS drug discovery. This review aims to update our previous findings on the clinical drug repurposing pipeline in schizophrenia. We examined studies conducted between 2018 and 2024, identifying 61 trials evaluating 40 unique repurposed drug candidates. These encompassed a broad range of pharmacological mechanisms, including immunomodulation, cognitive enhancement, and hormonal, metabolic, and neurotransmitter modulation. A notable development is the combination of the muscarinic modulators xanomeline, a compound with antipsychotic properties, and trospium, included to mitigate peripheral side effects, now approved by the FDA as the first antipsychotic drug in decades with a fundamentally novel mechanism of action. Moving beyond the traditional dopaminergic paradigm of schizophrenia, such findings highlight opportunities to improve treatment-resistant symptoms and alleviate adverse effects. Overall, the evolving drug repurposing landscape illustrates a significant shift in the rationale for schizophrenia drug development, highlighting the potential of in silico strategies, biomarker-based patient stratification, and personalized treatments that align with underlying pathophysiological processes.

To follow disease progression in a rat model of Type 2 diabetes using multimodal MRI to assess changes in brain structure and function.

Female rats (n = 20) were fed a high fat/high fructose diet or lab chow starting at 90 days of age. Diet fed rats were given streptozotocin to compromise pancreatic beta cells, while chow fed controls received vehicle. At intervals of 3, 6, 9, and 12 months, rats were tested for changes in behavior and sensitivity to pain. Brain structure and function were assessed using voxel based morphometry, diffusion weighted imaging and functional connectivity.

Diet fed rats presented with elevated plasma glucose levels as early as 3 months and a significant gain in weight by 6 months as compared to controls. There were no significant changes in cognitive or motor behavior over the yearlong study but there was a significant increase in sensitivity to peripheral pain in diet fed rats. There were region specific decreases in brain volume e.g., basal ganglia, thalamus and brainstem in diet fed rats. These same regions showed elevated measures of water diffusivity evidence of putative vasogenic edema. By 6 months, widespread hyperconnectivity was observed across multiple brain regions. By 12 months, only the cerebellum and hippocampus showed increased connectivity, while the hypothalamus showed decreased connectivity in diet fed rats.

Noninvasive multimodal MRI identified site specific changes in brain structure and function in a yearlong longitudinal study of Type 2 diabetes in rats. The identified diabetic-induced neuropathological sites may serve as biomarkers for evaluating the efficacy of novel therapeutics.

Schizoaffective disorder is a severe psychiatric condition characterized by mood disturbances and psychotic symptoms. Standard treatments, primarily pharmacological, often fail to control symptoms fully and can lead to significant metabolic side effects. Emerging evidence suggests that ketogenic metabolic therapy (KMT), also known as the ketogenic diet, may offer a powerful alternative to conventional treatments for mood components and resolve psychiatric symptoms in patients with schizoaffective disorder.

This case series investigates the effects of KMT on two individuals diagnosed with schizoaffective disorder who pursued this therapy due to the ineffectiveness of conventional treatments. Both case presentations followed a modified ketogenic diet with medical oversight. Symptom changes in mood were assessed using validated tools, including the Generalized Anxiety Disorder-7 (GAD-7), Depression Anxiety Stress Scales (DASS-42), PTSD Checklist for DSM-5 (PCL-5), and Patient Health Questionnaire-9 (PHQ-9).

Both case presentations experienced the complete cessation of psychotic symptoms and improvements in mood. Case 1, a 17-year-old female, achieved full remission of severe suicidal ideation, hallucinations, and anxiety within 6 weeks, with sustained improvements at a 24-week follow-up. Case 2, a 32-year-old female, achieved full remission of chronic psychotic and mood symptoms by 6 months. Patients either achieved full psychiatric deprescription or were in the process of deprescription at time of follow-up.

This case series demonstrates that ketogenic metabolic therapy can resolve chronic psychotic and mood symptoms in patients with schizoaffective disorder, leading to full remission and significant functional recovery and reported improvements in quality of life that extend beyond symptom control with standard of care interventions.

Almost all antipsychotics are associated with weight gain. Given the gravity of this side-effect and its consequences, it is imperative to understand the mechanisms involved. One mechanism that could contribute to this side effect is the impact of antipsychotics on eating-related outcomes.

We aimed to synthesise the available quantitative research on the effects of first- and second-generation antipsychotics on eating-related outcomes, and qualitative research exploring people's experiences with these medications in relation to appetite and eating behaviours (PROSPERO protocol CRD42022340211).

We searched Medline, PsycInfo, and Web of Science from inception to 9 May 2024. Quantitative data were synthesised without meta-analysis using vote counting based on direction of effect. Qualitative data were synthesised using thematic synthesis.

Searches identified 8,746 citations yielding 61 separate studies; 55 quantitative and 6 qualitative, published 1982-2024. Using GRADE, our assessment of the quantitative review findings ranged from low to very low-level certainty. Given the lack of direct evidence from high-quality placebo-controlled trials, it is pertinent to interpret the quantitative findings with caution. Using GRADE-CERQual, our assessment of the qualitative review findings ranged from low to very low-level certainty; these findings suggest that the relationship between antipsychotics and food intake is influenced by an interplay of individual, interpersonal and external factors, the most significant of which is food environment.

The internal validity of this review was affected by the serious limitations of the included quantitative studies and the paucity of qualitative evidence.

We used GRADE and GRADE-CERQual frameworks to enhance the transparency of our judgement of the certainty of the evidence. Lived experience perspectives were incorporated in different stages of the review to enhance its relevance and practical implications.

There is insufficient evidence from well-conducted studies to determine the effect of antipsychotics on eating-related outcomes.

People with severe-mental-illness (SMI), often defined as "schizophrenia-spectrum disorders and bipolar disorder", have increased premature mortality and elevated prevalence of diabetes compared with general population. Evidence indicated that one-third of their premature death was from cardiovascular diseases (CVD), with risk conferred by diabetes. Although earlier studies have examined SMI-associated diabetes-related outcomes, findings were inconsistent and not systematically evaluated. We systematically reviewed and quantitatively synthesized diabetes-related outcomes in patients with SMI (schizophrenia-spectrum disorders and bipolar disorder) by searching Embase, MEDLINE, PsycInfo, and Web-of-Science from inception to 31-March-2024, and included studies examining mortality and complication outcomes in SMI patients with co-occurring diabetes relative to patients with diabetes-only. Results were synthesized by random-effects models, with stratified-analyses by study-level characteristics. The study was registered with PROSPERO (CRD42023448490). Twenty-one studies involving 161,156 SMI patients with co-occurring diabetes were identified from ten regions. Regarding mortality risk, SMI-diabetes group exhibited increased risks of all-cause mortality (RR=1.77[95 % CI: 1.46-2.14]) and CVD-specific mortality (1.88[1.73-2.04]) relative to diabetes-only group. All-cause mortality risk was present in distinct regions and has persisted over time. Regarding complication risk, SMI-diabetes group showed higher risk of any complications (1.23[1.06-1.43]) than comparison, with stratified-analyses showing higher risk of metabolic-complications (1.84[1.58-2.15]), and lower likelihood of peripheral-vascular complications (0.91[0.84-0.99]), neuropathy (0.85[0.78-0.93]), and retinopathy (0.70[0.60-0.82]), albeit comparable cardiovascular-complications (1.04[0.89-1.22]), cerebrovascular-complications (1.07[0.86-1.33]), and nephropathy (0.92[0.72-1.17]). High heterogeneity was noted and could not be fully-explained by subgroup-analyses. Implementation of targeted interventions is needed to rectify their diabetes-related outcomes and mortality gap.

It has been well-established that the allostatic load (AL) index, a cumulative score of multi-system dysregulation in response to chronic stress, is significantly increased at the time of a psychiatric diagnosis. However, no studies have investigated if there is an association between the AL index in childhood and the later development of mental health symptoms in young adults.

Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a population cohort from Bristol, United Kingdom, we investigated the AL index at age 9 years and the risks for mental health symptoms at age 24 years. We used multinomial logistic regression analysis to investigate the association between AL threshold (categorised into bottom third: AL index ≤ 7, middle third: AL index = 7.1-9.9, and top third: AL index ≥ 10) and mental health symptoms while adjusting for sex, the age of mother at delivery, and social class. We used a relative risk ratio (RRR) and 95 % confidence interval(CI) for each variable. We further investigated the association between adverse childhood experiences (ACEs) and mental health symptoms.

We identified a significant association between sex and mental health symptoms, with more females (59 % vs 41 %) showing mental health symptoms than males. We found no direct association between the AL index at age 9 and the later development of mental health symptoms. However, an RRR analysis showed that individuals in the middle and the top third of the AL index had an RRR of 1.99 and 2.20, respectively, to develop mental health symptoms if they were females. We found that individuals who experienced ACE had a much higher risk of developing mental health symptoms as young adults, with the adjusted RRR of 5.39 (95 % CI: 3.00;9.67), 6.79 (95 % CI: 2.55; 18.1), and 2.10 (95 % CI: 0.37;11.8) for neglect, physical and sexual abuse, respectively, in individuals with mood disorder symptoms. The adjusted RRR for neglect and physical and sexual abuse in individuals with psychotic symptoms was 0.99 (95 % CI: 0.37; 2.59), 2.92 (95 % CI: 0.35; 24.4), and 10.5 (95 % CI: 0.99; 112), respectively.

Although the AL index in childhood was not directly associated with the later development of psychotic and mood disorder symptoms in this cohort, females in the higher tertiles of the AL index measured at 9 years of age had an elevated risk of mental health symptoms as young adults. In line with previous work, a strong association was identified between childhood adversity and mental health symptoms in young adulthood. These results highlight the importance of considering the impact of early stress on biological embedding and the later emergence of mental health problems, especially in females.

Rising studies have consistently reported gut bacteriome alterations in schizophrenia (SCZ). However, little is known about the role of the gut virome on shaping the gut bacteriome in SCZ. Here in, we sequenced the fecal virome, bacteriome, and host peripheral metabolome in 49 SCZ patients and 49 health controls (HCs). We compared the gut bacterial community composition and specific abundant bacteria in SCZ patients and HCs. Specific gut viruses and host peripheral metabolites co-occurring with differential bacteria were identified using Multiple Co-inertia Analysis (MCIA). Additionally, we construct a latent serial mediation model (SMM) to investigate the effect of the gut virome on SCZ through the bacteriome and host metabolic profile. SCZ patients exhibited a decreased gut bacterial β-diversity compared to HCs, with seven differentially abundant bacteria, including Coprobacillaceae, Enterococcaceae etc. Gut viruses including Suoliviridae and Rountreeviridae, co-occur with these SCZ-related bacteria. We found that the viral-bacterial transkingdom correlations observed in HCs were dramatically lost in SCZ. The altered correlations profile observed in SCZ may impact microbiota-derived peripheral metabolites enriched in the bile acids pathway, eicosanoids pathway, and others, contributing to host immune dysfunction and inflammation. The SMM model suggested potential causal chains between gut viruses and SCZ, indicating that the effect of gut virome on SCZ is significantly mediated by bacteriome and metabolites. In conclusion, these findings provide a comprehensive perspective on the role of gut microbiota in the pathogenesis of SCZ. They reveal that patients with schizophrenia harbor an abnormal virome-bacteriome ecology, shedding light on the potential development of microbial therapeutics.

Convergent evidence shows the presence of brain metabolic abnormalities in psychotic disorders. This study examined brain reductive stress and energy metabolism in people with psychotic disorders with impaired or average range cognition. We hypothesized that global cognitive impairment would be associated with greater brain metabolic dysregulation.

Participants with affective and non-affective psychosis (n = 62) were administered the MATRICS Consensus Cognitive Battery (MCCB) and underwent a 31P-magnetic resonance spectroscopy scan at 4T. We used a cluster-analysis approach to identify 2 clusters of participants with and without cognitive dysfunction. We compared clusters on brain redox balance or reductive stress, measured by the ratio of nicotinamide adenine dinucleotide (NAD+) and its reduced form NADH, in addition to creatine kinase (CK) enzymatic activity and pH.

The mean (SD) age of participants was 25.1 (6.3) years. The mean NAD+/NADH ratio differed between groups, with lower NAD+/NADH ratio, suggesting more reductive stress, in the impaired cognitive cluster (t = -2.60, P = .01). There was also a significant reduction in CK activity in the impaired cognitive cluster (t = -2.19, P = .03). Intracellular pH did not differ between the 2 cluster groups (t = 1.31, P = .19). The clusters did not significantly differ on severity of mood and psychotic symptomatology or other measures of illness severity.

Our results demonstrate that psychotic disorders with greater cognitive impairment have greater brain metabolic dysregulation, with more reductive stress and decrease in energy metabolic rate markers. This provides new evidence for the potential of emerging metabolic therapies to treat cognitive deficits in psychotic disorders.

Individuals with first-episode psychosis (FEP) face an increased risk of physical comorbidities, notably cardiovascular diseases, metabolic disorders, respiratory disorders, and certain types of cancer. Previous reviews report pooled physical health prevalence from chronic psychosis and FEP groups. By contrast, this review will focus on antipsychotic-naïve FEP cohorts and incorporate data from observational longitudinal studies and antipsychotic intervention studies to understand the progression of physical health comorbidities from the onset to later stages of psychosis. This review aims to examine the short-, medium-, and long-term period prevalence of these comorbidities in FEP and variations related to demographic factors.

Using the PRISMA and MOOSE guidelines, Medline, Embase, PsycINFO, and CINAHL+, as well as Clinical Trials gov.uk, OpenGrey, WHO International Clinical Trials Registry Platform, Current Controlled Trials, United States National Institute of Health Trials Registry, and the Irish Health Repository, will be searched from inception. Longitudinal studies and antipsychotic intervention studies monitoring health outcomes in antipsychotic naïve FEP individuals will be eligible for inclusion. Two reviewers will independently screen titles, abstracts, and full-text articles. Risk of bias will be assessed using the Joanna Briggs Institute Critical Appraisal Checklist. A meta-analysis of the short-, medium-, and long-term prevalence of cardiovascular, metabolic, cancer, and respiratory outcomes and a narrative synthesis will be conducted. Where feasible, a meta-regression on the impact of demographic variables will be conducted. Potential limitations include the risk of diagnostic heterogeneity across studies and possible underreporting of certain comorbidities.

This systematic review will clarify the progression of physical health comorbidities in FEP, informing early intervention strategies and policies. Subsequent findings will be submitted to a leading journal, supplemented by a recovery education module and a lay summary for wider dissemination.

The study was registered in PROSPERO, the International Prospective Register of Systematic Reviews ( CRD42023431072; 17/06/2023).

This study aimed to evaluate the predictive validity and discriminatory ability of clinical outcomes, inflammatory activity, oxidative and vascular damage, and metabolic mechanisms for detecting significant improve maximum heart rate after physical activity training in individuals with psychiatric disorders and obesity comorbid using a longitudinal design and transdiagnostic perspective.

Patients with major depressive disorder, bipolar disorder and, schizophrenia and with comorbid obesity (n = 29) were assigned to a 12-week structured physical exercise program. Peripheral blood biomarkers of inflammation, oxidative stress, vascular mechanisms, and metabolic activity, as well as neurocognitive and functional performance were assessed twice, before and after intervention. Maximum heart rate was considered a marker of effectiveness of physical activity. Mixed one-way analysis of variance and linear regression analyses were performed.

Individuals with psychiatric disorders and comorbid obesity exhibited an improvement in cognition, mood symptoms and body mass index, increase anti-inflammatory activity together with enhancement of the oxidative and cardiovascular mechanisms after physical activity training (p<0.05 to 0.0001; d = 0.47 to 1.63). A better clinical outcomes along with regulation of inflammatory, oxidative, and cardiovascular mechanisms were critical for predicting significant maximum heart rate variation over time (χ2 = 32.2 to 39.0, p < 0.0001).

The regulation of the anti-inflammatory mechanisms may be essential for maintained of healthy physical activity across psychiatric disorders and obesity. Likewise, inflammatory activity, oxidative stress, vascular and cardio-metabolic mechanisms may be a useful to identify individuals at greater risk of multi-comorbidity.

Administration of olanzapine (OLA) is closely associated with obesity and glycolipid abnormalities in patients with schizophrenia (SCZ), although the exact molecular mechanisms remain elusive.

We conducted comprehensive animal and molecular experiments to elucidate the mechanisms underlying OLA-induced weight gain.

We investigated the mechanisms of OLA-induced adipogenesis and lipid storage by employing a real-time ATP production rate assay, glucose uptake test, and reactive oxygen species (ROS) detection in 3T3-L1 cells and AMSCs. Rodent models were treated with OLA using various intervention durations, dietary patterns (normal diets/western diets), and drug doses. We assessed body weight, epididymal and liver fat levels, and metabolic markers in both male and female mice.

OLA accelerates adipogenesis by directly activating glycolysis and its downstream PI3K signaling pathway in differentiated adipocytes. OLA promotes glucose uptake in differentiated 3T3-L1 preadipocytes. In mouse models with normal glycolipid metabolism, OLA administration failed to increase food intake and weight gain despite elevated GAPDH expression, a marker related to glycolysis and PI3K-AKT. This supports the notion that glycolysis plays a significant role in OLA-induced metabolic dysfunction.

OLA induces glycolysis and activates the downstream PI3K-AKT signaling pathway, thereby promoting adipogenesis.

With the frequent use of antipsychotics, the metabolic disorder (MetD) caused by drugs has received increasing attention. However, the mechanism of drug-induced MetD is still unclear and is being explored. Keeping abreast of the progress and trending knowledge in this area is conducive to further work.

The aim of this study is to analyze the latest status and trends of research on antipsychoticinduced metabolic disorder (AIMetD) by bibliometric and visual analysis.

3478 publications of AIMetD from 2006 to 2021 were retrieved from the Web of Science Core Collection database. R-biblioshiny was used for descriptive analysis, CiteSpace for cooperative network, co-citation analysis and burst detection, and VOSviewer for co-occurrence keywords was used.

Since 2006, the publications have been growing fluctuantly. These studies have extensive cooperation among countries/regions. The most influential country/region, institution and author are the USA, King's College London and Christoph U Correll. Analysis of references shows the largest cluster of "antipsychotic-induced metabolic dysfunction", which is an important basis for MetD. The recent contents of the burst citation are related to "glucose homeostasis" and "cardiovascular metabolism". Several bursting keywords were discerned at the forefront, including "LC-MS/MS", "major depressive disorder", "expression", and "homeostasis".

The AIMetD study is in a state of sustained development. Close cooperation between countries/ regions has promoted progress. For grasping the foundation, development, and latest trends of AIMetD, it is recommended to focus on active institutions and authors. Based on AIMetD, subdivision areas such as "LC-MS/MS", "expression", and "homeostasis" are forefronts that deserve constant attention.

Metabolic syndrome (MetS), a condition that includes several risk factors specific for cardiovascular disease, is commonly detected among patients with schizophrenia (SCZ). This study elucidated the factors contributing to the development and severity of MetS in first-treatment drug-naïve (FTDN) patients with SCZ.

The study enrolled 668 individuals with FTDN SCZ, aged 18-49 years, who had no exposure to antipsychotic medications and been hospitalized between February 2017 and June 2022 at the largest psychiatric specialty institution in central China. Patient sociodemographic and general clinical data were collected, and their psychopathology scores and illness severity were assessed using the Positive and Negative Symptom Scale (PANSS) and Clinical Global Impression Scale-Severity of Illness (CGI-SI), respectively. MetS score was calculated to determine the disease severity.

The prevalence of MetS among this study population was 10.93%. Binary logistic regression analysis revealed onset age, female sex, total cholesterol, and red blood and white blood cell counts as risk factors for MetS, and deemed free tetraiodothyronine (FT4) and CGI-SI score as protective factors. Multiple linear regression analysis result confirmed older SCZ onset age as a risk factor for elevated MetS score.

This study determined the prevalence of MetS in patients with FTDN SCZ and revealed the factors that influence the occurrence and severity of the disease. These findings will allow development of specific prevention and treatment strategies in clinical practice.

The (MTHFR) C677T gene polymorphism is associated with neurological disorders and schizophrenia. Patients diagnosed with schizophrenia and schizoaffective disorder and controls (n 134) had data collected for risk factors, molecular and neuro-sensory variables, symptoms, and functional outcomes. Promising gene variant-related predictive biomarkers were identified for diagnosis by Receiver Operating Characteristics and for illness duration by linear regression. These were then analyzed using Spearman's correlation in relation to the duration of illness. Significant correlations were ranked by strength and plotted on graphs for each MTHFR C677T variant. Homozygous MTHFR 677 TT carriers displayed a mid-illness switch to depression, with suicidality and a late-phase shift from lower to higher methylation, with activated psychosis symptoms. MTHFR 677 CC variant carriers displayed significant premorbid correlates for family history, developmental disorder, learning disorder, and head injury. These findings align with those of low methylation, oxidative stress, multiple neuro-sensory processing deficits, and disability outcomes. Heterozygous MTHFR 677 CT carriers displayed multiple shifts in mood and methylation with multiple adverse outcomes. The graphically presented ranked biomarker correlates for illness duration allow a perspective of psychosis development across gene variants, with the potential for phase of illness monitoring and new therapeutic insights to prevent or delay psychosis and its adverse outcomes.

Schizophrenia is a common chronic psychiatric disorder that causes age-related dysfunction. The life expectancy in patients with schizophrenia is ≥10 years shorter than that in the general population because of the higher risk of other diseases, such as cardiovascular diseases. Aging studies based on DNA methylation status have received considerable attention. Several epigenetic age accelerations and predicted values of aging-related proteins (GrimAge and GrimAge2 components) have been analyzed in multiple diseases. However, no studies have investigated up to GrimAge and GrimAge2 components between patients with schizophrenia and controls. Therefore, we aimed to conduct multiple regression analyses to investigate the association between schizophrenia and epigenetic age accelerations and GrimAge and GrimAge2 components in seven cohorts. Furthermore, we included patients with first-episode psychosis whose illness duration was often shorter than schizophrenia in our analysis. We integrated these results with meta-analyses, noting the acceleration of GrimAge, GrimAge2, and DunedinPACE, and increase in adrenomedullin, beta-2 microglobulin, cystatin C, and plasminogen activation inhibitor-1 levels, in patients with schizophrenia or first-episode psychosis. These results corroborated the finding that patients with schizophrenia had an increased risk of diabetes, cardiovascular disease, and cognitive dysfunction from a biological perspective. Patients with schizophrenia and first-episode psychosis showed differences in the results when compared with controls. Such analyses may lead to the development of novel therapeutic targets to patients with schizophrenia or relevant diseases from the perspective of aging in the future.

The glymphatic system (GS), a brain waste clearance pathway, is disrupted in various neurodegenerative and vascular diseases. As schizophrenia shares clinical characteristics with these conditions, we hypothesized GS disruptions in patients with schizophrenia spectrum disorder (SCZ-SD), reflected in increased brain macromolecule (MM) and decreased diffusion-tensor-image-analysis along the perivascular space (DTI-ALPS) index.

Forty-seven healthy controls (HCs) and 103 patients with SCZ-SD were studied. Data included 135 proton magnetic resonance spectroscopy (1H-MRS) sets, 96 DTI sets, with 79 participants contributing both. MM levels were quantified in the dorsal-anterior cingulate cortex (dACC), dorsolateral prefrontal cortex, and dorsal caudate (point resolved spectroscopy, echo-time = 35ms). Diffusivities in the projection and association fibers near the lateral ventricle were measured to calculate DTI-ALPS indices. General linear models were performed, adjusting for age, sex, and smoking. Correlation analyses examined relationships with age, illness duration, and symptoms severity.

MM levels were not different between patients and HCs. However, left, right, and bilateral DTI-ALPS indices were lower in patients compared with HCs (P < .001). In HCs, age was positively correlated with dACC MM and negatively correlated with left, right, and bilateral DTI-ALPS indices (P < .001). In patients, illness duration was positively correlated with dACC MM and negatively correlated with the right DTI-ALPS index (P < .05). In the entire population, dACC MM and DTI-ALPS indices showed an inverse correlation (P < .01).

Our results suggest potential disruptions in the GS of patients with SCZ-SD. Improving brain's waste clearance may offer a potential therapeutic approach for patients with SCZ-SD.

This review article explores the transformative potential of dynamic, real-time biosensing in biorhythm tracking for psychiatric disorders. Psychiatric diseases, characterized by a complex, heterogeneous, and multifactorial pathophysiology, pose challenges in both diagnosis and treatment. Common denominators in the pathophysiology of psychiatric diseases include disruptions in the stress response, sleep-wake cycle, energy metabolism, and immune response: all of these are characterized by a strong biorhythmic regulation (e.g., circadian), leading to dynamic changes in the levels of biomarkers involved. Technological and practical limitations have hindered the analysis of such dynamic processes to date. The integration of biosensors marks a paradigm shift in psychiatric research. These advanced technologies enable multiplex, non-invasive, and near-continuous analysis of biorhythmic biomarkers in real time, overcoming the constraints of conventional approaches. Focusing on the regulation of the stress response, sleep/wake cycle, energy metabolism, and immune response, biosensing allows for a deeper understanding of the heterogeneous and multifactorial pathophysiology of psychiatric diseases. The potential applications of nanobiosensing in biorhythm tracking, however, extend beyond observation. Continuous monitoring of biomarkers can provide a foundation for personalized medicine in Psychiatry, and allow for the transition from syndromal diagnostic entities to pathophysiology-based psychiatric diagnoses. This evolution promises enhanced disease tracking, early relapse prediction, and tailored disease management and treatment strategies. As non-invasive biosensing continues to advance, its integration into biorhythm tracking holds promise not only to unravel the intricate etiology of psychiatric disorders but also for ushering in a new era of precision medicine, ultimately improving the outcomes and quality of life for individuals grappling with these challenging conditions.

Type 2 diabetes mellitus (T2DM) and its related complications are associated with schizophrenia. However, the relationship between antipsychotic medications (APs) and T2DM risk remains unclear. In this population-based, retrospective cohort study across the country, we investigated schizophrenia and the effect of APs on the risk of T2DM, and glucose homeostasis-related gene expression.

We used information from the Longitudinal Health Insurance Database of Taiwan for individuals newly diagnosed with schizophrenia (N = 4,606) and a disease-free control cohort (N = 4,606). The differences in rates of development of T2DM between the two cohorts were assessed using a Cox proportional hazards regression model. The effects of APs on the expression of glucose homeostasis-related genes in liver and muscle cell lines were assessed using quantitative real-time PCR.

After controlling potential associated confounding factors, the risk of T2DM was higher in the case group than that in the control group [adjusted hazard ratio (aHR), 1.80, p < 0.001]. Moreover, the likelihood of T2DM incidence in patients with schizophrenia without AP treatment (aHR, 2.83) was significantly higher than that in non-schizophrenia controls and those treated with APs (aHR ≤ 0.60). In an in vitro model, most APs did not affect the expression of hepatic gluconeogenesis genes but upregulated those beneficial for glucose homeostasis in muscle cells.

This study demonstrates the impact of schizophrenia and APs and the risk of developing T2DM in Asian populations. Unmeasured confounding risk factors for T2DM may not have been included in the study. These findings may help psychiatric practitioners identify patients at risk of developing T2DM.

First-episode antipsychotics-naïve schizophrenia (FEAN-SCZ) is associated with abnormalities in glucose and lipid metabolism. While sex differences in the incidence and severity of SCZ and metabolic abnormalities have been documented, the specific metabolic abnormalities between the sexes remain unclear. The study aimed to investigate sex-specific differences in plasma glycolipid profiles in FEAN-SCZ patients.

A total of 172 FEAN-SCZ patients (male/female: 83/89) and 31 healthy controls (male/female: 14/17) were recruited. Psychopathology assessment was conducted using the Positive and Negative Syndrome Scale (PANSS). Glycolipid profiles, including oral glucose tolerance test (OGTT), fasting glucose, insulin, total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) were examined in all participants.

FEAN patients displayed significantly higher fasting and 2-hour glucose levels compared to healthy controls (both p < 0.001). Impaired glucose tolerance (IGT) prevalence in male patients was 24.1 % (n = 20) and 25.9 % (n = 23) in females, contrasting with 0 % (n = 0) in the control group. FEAN patients exhibited elevated blood insulin and TC levels (both p < 0.05) and increased insulin resistance measured by HOMA-IR (p < 0.01). Among male patients, those with IGT had significantly higher TC, TG and LDL levels than non-IGT patients (all p < 0.05), while no significant differences were observed in female patients between IGT and non-IGT groups. Body mass index (BMI), TG and HDL levels were identified as significant predictors of IGT in male FEAN patients.

IGT is present in a subset of FEAN-SCZ patients. Male patients with IGT exhibit distinct alterations in plasma lipid profiles compared to non-IGT patients.

Major psychotic disorders (MPD), including schizophrenia (SCZ) and schizoaffective disorder (SAD), are severe neuropsychiatric conditions with unclear causes. Understanding their pathophysiology is essential for better diagnosis, treatment, and prognosis. Recent research highlights the role of inflammation and the immune system, particularly the Interleukin 17 (IL-17) family, in these disorders. Elevated IL-17 levels have been found in MPD, and human IL-17 A antibodies are available. Changes in chemokine levels, such as CCL20, are also noted in SCZ. This study investigates the relationship between serum levels of IL-17 A and CCL20 in MPD patients and their clinical characteristics.

We conducted a case-control study at the Ibn Sina Psychiatric Hospital (Mashhad, Iran) in 2023. The study involved 101 participants, of which 71 were MPD patients and 30 were healthy controls (HC). The Positive and Negative Symptom Scale (PANSS) was utilized to assess the symptoms of MPD patients. Serum levels of CCL20 and IL-17 A were measured using Enzyme-Linked Immunosorbent Assay (ELISA) kits. We also gathered data on lipid profiles and Fasting Blood Glucose (FBS).

The mean age of patients was 41.04 ± 9.93 years. The median serum levels of CCL20 and IL-17 A were significantly elevated in MPD patients compared to HC (5.8 (4.1-15.3) pg/mL and 4.2 (3-5) pg/mL, respectively; p < 0.001). Furthermore, CCL20 and IL-17 A levels showed a positive correlation with the severity of MPD. MPD patients also had significantly higher FBS, cholesterol, and Low-Density Lipoprotein (LDL) levels, and lower High-Density Lipoprotein (HDL) levels compared to HC. No significant relationship was found between PANSS components and blood levels of IL17 and CCL20.

The current study revealed that the serum levels of IL-17 A and CCL20 in schizophrenia patients are higher than those in the control group. Metabolic factors such as FBS, cholesterol, HDL, and LDL also showed significant differences between MPD and HC. In conclusion, the findings suggest that these two inflammatory factors could serve as potential therapeutic targets and prognostic biomarkers for schizophrenia.

Antipsychotic drugs may have adverse effects on the components of metabolic syndrome. Previous studies have shown that changes in the intestinal microbiome are associated with metabolic disturbances in patients with schizophrenia. The objective of this study was to determine the effects of synbiotics on the components of metabolic syndrome as primary outcomes in patients with schizophrenia. Secondary outcomes were HbA1c, insulin resistance, LDL-c, and anthropometric measurements.

In this double-blind, placebo-controlled trial, seventy patients with schizophrenia receiving antipsychotic drugs who had at least two criteria of metabolic syndrome were randomly divided into two groups to receive either two capsules of a synbiotic supplement or a placebo daily for 8 weeks. Anthropometric indices and biochemical parameters were measured at baseline and after the intervention.

Fifty-five patients completed the study. The synbiotic supplement significantly decreased waist circumference and HbA1C compared to placebo (-2.66 ± 4.20 vs. 3.03 ± 4.50 and - 0.26 ± 0.54 vs. 0.20 ± 0.75, respectively). Although BMI did not change significantly in the synbiotic + antipsychotic group, it increased in the placebo + antipsychotic group (-0.37 ± 1.00 vs. 0.61 ± 1.09 P < 0.5). LDL-c and triglyceride (TG) levels decreased significantly in the synbiotic + antipsychotic group, but the change was not significantly different from that of the placebo + antipsychotic group. FBS, HDL-c, systolic and diastolic blood pressure, insulin resistance, and total cholesterol were not significantly different between the two groups after intervention.

Synbiotic supplement may decrease waist circumference, HbA1c, LDL and TG and prevent BMI increase in patients receiving antipsychotic drugs.

Iranian Registry of Clinical Trials (IRCT Number: IRCT20090901002394N45), Date: 26-12-2019.

Schizophrenia is a chronic, neurodevelopmental disorder with unknown aetiology and pathophysiology that emphasises the role of neurotransmitter imbalance and abnormalities in synaptic plasticity. The currently used pharmacological approach, the antipsychotic drugs, which have limited efficacy and an array of side-effects, have been developed based on the neurotransmitter hypothesis. Recent research has uncovered systemic and brain abnormalities in glucose and energy metabolism, focusing on altered glycolysis and mitochondrial oxidative phosphorylation. These findings call for a re-conceptualisation of schizophrenia pathophysiology as a progressing bioenergetics failure. In this review, we provide an overview of the fundamentals of brain bioenergetics and the changes identified in schizophrenia. We then propose a new explanatory framework positing that schizophrenia is a disease of impaired dynamic metabolic flexibility, which also reconciles findings of abnormal glucose and energy metabolism in the periphery and in the brain along the course of the disease. This evidence-based framework and testable hypothesis has the potential to transform the way we conceptualise this debilitating condition and to develop novel treatment approaches.

The application of ketogenic dietary interventions to mental health treatments is increasingly acknowledged within medical and psychiatric fields, yet its exploration in clinical psychology remains limited. This article discusses the potential implications of ketogenic diets, traditionally utilized for neurological disorders, within broader mental health practices.

This article presents a perspective based on existing ketogenic diet research on historical use, biological mechanisms, and therapeutic benefits. It examines the potential application of these diets in mental health treatment and their relevance to clinical psychology research and practice.

The review informs psychologists of the therapeutic benefits of ketogenic diets and introduces to the psychology literature the underlying biological mechanisms involved, such as modulation of neurotransmitters, reduction of inflammation, and stabilization of brain energy metabolism, demonstrating their potential relevance to biopsychosocial practice in clinical psychology.

By considering metabolic therapies, clinical psychologists can broaden their scope of biopsychosocial clinical psychology practice. This integration provides a care model that incorporates knowledge of the ketogenic diet as a treatment option in psychiatric care. The article emphasizes the need for further research and training for clinical psychologists to support the effective implementation of this metabolic psychiatry intervention.

A wide array of biological abnormalities in psychotic illness appear to reflect non-cerebral involvement. This review first outlines the evidence for such a whole-body concept of schizophrenia pathobiology, focusing particularly on cardiovascular disease, metabolic syndrome and diabetes, immunity and inflammation, cancer, and the gut-brain axis. It then considers the roles of miRNAs in general and of miRNA-143 in particular as they relate to the epidemiology, pathobiology, and treatment of schizophrenia. This is followed by notable evidence that miRNA-143 is also implicated in each of these domains of cardiovascular disease, metabolic syndrome and diabetes, immunity and inflammation, cancer, and the gut-brain axis. Thus, miRNA-143 is an exemplar of what may be a class of molecules that play a role across the multiple domains of bodily dysfunction that appear to characterize a whole-body perspective of illness in schizophrenia. Importantly, the existence of such an exemplary molecule across these multiple domains implies a coordinated rather than stochastic basis. One candidate process would be a pleiotropic effect of genetic risk for schizophrenia across the whole body.

The metabolic syndrome in patients with schizophrenia has consistently been a challenge for clinicians. Previous studies indicate that individuals with schizophrenia are highly prone to developing type 2 diabetes mellitus (T2DM). In recent years, a continuous stream of new observational studies has been reported, emphasizing the pressing need for clinicians to gain a more precise understanding of the association between schizophrenia and T2DM. The objective of this meta-analysis is to integrate new observational studies and further explore the potential link between schizophrenia and the risk of T2DM.

We conducted a comprehensive search of PubMed, Cochrane Library, Embase, and Web of Science using medical subject headings (MeSH) and relevant keywords. The risk of bias in cohort studies and case-control studies was assessed using the Newcastle-Ottawa Scale (NOS), while cross-sectional studies were evaluated using the Agency for Healthcare Research and Quality scale (AHRQ), scoring was based on the content of the original studies. A fixed-effects model was employed if P > 0.1 and I2 ≤ 50%, indicating low heterogeneity. Conversely, a random-effects model was utilized if I2 > 50%, indicating substantial heterogeneity. Publication bias was assessed using funnel plots and Egger's test. Statistical analyses were carried out using Stata statistical software version 14.0.

This meta-analysis comprised 32 observational studies, involving a total of 2,007,168 patients with schizophrenia and 35,883,980 without schizophrenia, published from 2004 to 2023. The pooled analysis revealed a significant association between a history of schizophrenia and an increased risk of T2DM (Odds Ratio [OR] = 2.15; 95% Confidence Interval [CI]: 1.83-2.52; I2 = 98.9%, P < 0.001). Stratified by gender, females with schizophrenia (OR = 2.12; 95% CI: 1.70-2.64; I2 = 90.7%, P < 0.001) had a significantly higher risk of T2DM than males (OR = 1.68; 95% CI: 1.39-2.04; I2 = 91.3%, P < 0.001). Regarding WHO regions, EURO (OR = 2.73; 95% CI: 2.23-3.35; I2 = 97.5%, P < 0.001) exhibited a significantly higher risk of T2DM compared to WPRO (OR = 1.72; 95% CI: 1.32-2.23; I2 = 95.2%, P < 0.001) and AMRO (OR = 1.82; 95% CI: 1.40-2.37; I2 = 99.1%, P < 0.001). In terms of follow-up years, the >20 years subgroup (OR = 3.17; 95% CI: 1.24-8.11; I2 = 99.4%, P < 0.001) showed a significantly higher risk of T2DM than the 10-20 years group (OR = 2.26; 95% CI: 1.76-2.90; I2 = 98.6%, P < 0.001) and <10 years group (OR = 1.68; 95% CI: 1.30-2.19; I2 = 95.4%, P < 0.001).

This meta-analysis indicates a strong association between schizophrenia and an elevated risk of developing diabetes, suggesting that schizophrenia may function as an independent risk factor for T2DM.

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023465826.

Increasing evidences suggest that nonalcoholic fatty liver disease (NAFLD) is associated with neuropsychiatric disorders. Nevertheless, whether there were causal associations between them remained vague. A causal association between neuropsychiatric disorders and NAFLD was investigated in this study.

We assessed the published genome-wide association study summary statistics for NAFLD, seven mental disorder-related diseases and six central nervous system dysfunction-related diseases. The causal relationships were first assessed using two-sample and multivariable Mendelian randomization (MR). Then, sensitivity analyses were performed, followed by a reverse MR analysis to determine whether reverse causality is possible. Finally, we performed replication analyses and combined the findings from the above studies.

Our meta-analysis results showed NAFLD significantly increased the risk of anxiety disorders (OR = 1.016, 95% CI = 1.010-1.021, P value < 0.0001). In addition, major depressive disorder was the potential risk factor for NAFLD (OR = 1.233, 95% CI = 1.063-1.430, P value = 0.006). Multivariable MR analysis showed that the causal effect of major depressive disorder on NAFLD remained significant after considering body mass index, but the association disappeared after adjusting for the effect of waist circumference. Furthermore, other neuropsychiatric disorders and NAFLD were not found to be causally related.

These results implied causal relationships of NAFLD with anxiety disorders and Major Depressive Disorder. This study highlighted the need to recognize and understand the connection between neuropsychiatric disorders and NAFLD to prevent the development of related diseases.

Schizophrenia, schizoaffective disorder, and bipolar affective disorder are debilitating psychiatric conditions characterized by a chronic pattern of emotional, behavioral, and cognitive disturbances. Shared psychopathology includes the pre-eminence of altered affective states, disorders of thoughts, and behavioral control. Additionally, those conditions share epidemiological traits, including significant cardiovascular, metabolic, infectious, and respiratory co-morbidities, resulting in reduced life expectancy of up to 25 years. Nutritional ketosis has been successfully used to treat a range of neurological disorders and preclinical data have convincingly shown potential for its use in animal models of psychotic disorders. More recent data from open clinical trials have pointed toward a dramatic reduction in psychotic, affective, and metabolic symptoms in both schizophrenia and bipolar affective disorder.

to investigate the effects of nutritional ketosis via a modified ketogenic diet (MKD) over 14 weeks in stable community patients with bipolar disorder, schizoaffective disorder, or schizophrenia.

A randomized placebo-controlled clinical trial of 100 non-hospitalized adult participants with a diagnosis of bipolar disorder, schizoaffective disorder, or schizophrenia who are capable of consenting and willing to change their diets.

Dietitian-led and medically supervised ketogenic diet compared to a diet following the Australian Guide to Healthy Eating for 14 weeks.

The primary outcomes include psychiatric and cognitive measures, reported as symptom improvement and functional changes in the Positive and Negative Symptoms Scale (PANSS), Young Mania Rating Scale (YMS), Beck Depression Inventory (BDI), WHO Disability Schedule, Affect Lability Scale and the Cambridge Cognitive Battery. The secondary metabolic outcomes include changes in body weight, blood pressure, liver and kidney function tests, lipid profiles, and markers of insulin resistance. Ketone and glucose levels will be used to study the correlation between primary and secondary outcomes. Optional hair cortisol analysis will assess long-term stress and variations in fecal microbiome composition. Autonomic nervous system activity will be measured via wearable devices (OURA ring and EMBRACE wristband) in the form of skin conductance, oximetry, continuous pulse monitoring, respiratory rate, movement tracking, and sleep quality. Based on the encouraging results from established preclinical research, clinical data from other neurodevelopment disorders, and open trials in bipolar disorder and schizophrenia, we predict that the ketogenic metabolic therapy will be well tolerated and result in improved psychiatric and metabolic outcomes as well as global measures of social and community functioning. We additionally predict that a correlation may exist between the level of ketosis achieved and the metabolic, cognitive, and psychiatric outcomes in the intervention group.

Major depressive disorder (MDD) and obesity have a complex bidirectional relationship. However, most studies do not assess increased appetite or weight as a depressive symptom due to limitations in rating scales. Here we aimed to analyze frequently employed depressive-symptom scales and discuss the relevance of weight and appetite assessment items. To elaborate this perspective, we searched for validated questionnaires and scales evaluating depressive symptoms in English. We analyzed appetite and weight items from 20 depressive-symptoms rating scales. Only 8 of 20 rating scales assessed for increased weight or appetite. The scales reported in the literature as the most employed in antidepressants efficacy trials do not assess increased appetite or weight. The current use of rating scales limits our understanding of the relationship between MDD, antidepressants, and obesity. It is necessary to improve our weight and appetite measurements in MDD to clarify the respective impact of depressive symptoms and antidepressants on weight change.

Altered hippocampal morphology and metabolic pathology, but also hippocampal circuit dysfunction, are established phenomena seen in psychotic disorders. Thus, we tested whether hippocampal subfield volume deficits link with deviations in glucose metabolism commonly seen in early psychosis, and whether the glucose parameters or subfield volumes change during follow-up period using one-year longitudinal study design of 78 first-episode psychosis patients (FEP), 48 clinical high-risk patients (CHR) and 83 controls (CTR). We also tested whether hippocampal morphology and glucose metabolism relate to clinical outcome. Hippocampus subfields were segmented with Freesurfer from 3T MRI images and parameters of glucose metabolism were determined in fasting plasma samples. Hippocampal subfield volumes were consistently lower in FEPs, and findings were more robust in non-affective psychoses, with strongest decreases in CA1, molecular layer and hippocampal tail, and in hippocampal tail of CHRs, compared to CTRs. These morphometric differences remained stable at one-year follow-up. Both non-diabetic CHRs and FEPs had worse glucose parameters compared to CTRs at baseline. We found that, insulin levels and insulin resistance increased during the follow-up period only in CHR, effect being largest in the CHRs converting to psychosis, independent of exposure to antipsychotics. The worsening of insulin resistance was associated with deterioration of function and symptoms in CHR. The smaller volume of hippocampal tail was associated with higher plasma insulin and insulin resistance in FEPs, at the one-year follow-up. Our longitudinal study supports the view that temporospatial hippocampal subfield volume deficits are stable near the onset of first psychosis, being more robust in non-affective psychoses, but less prominent in the CHR group. Specific subfield defects were related to worsening glucose metabolism during the progression of psychosis, suggesting that hippocampus is part of the circuits regulating aberrant glucose metabolism in early psychosis. Worsening of glucose metabolism in CHR group was associated with worse clinical outcome measures indicating a need for heightened clinical attention to metabolic problems already in CHR.

Schizophrenia is a disease with a complex etiology that significantly impairs the functioning of patients. In recent years, there has been increasing focus on the importance of the gut microbiota in the context of the gut-brain axis. In our study, we analyzed data on the gut-brain axis in relation to schizophrenia, as well as the impacts of eating habits, the use of various supplements, and diets on schizophrenia. Additionally, the study investigated the impact of antipsychotics on the development of metabolic disorders, such as diabetes, dyslipidemia, and obesity. There may be significant clinical benefits to be gained from therapies supported by supplements such as omega-3 fatty acids, B vitamins, and probiotics. The results suggest the need for a holistic approach to the treatment of schizophrenia, incorporating both drug therapy and dietary interventions.

Evidence from epidemiological, clinical, and biological research resulted in the immune hypothesis: the hypothesis that immune system dysfunction is involved in the pathophysiology of schizophrenia spectrum disorders (SSD). The promising implication of this hypothesis is the potential to use existing immunomodulatory treatment for innovative interventions for SSD. Here, we provide a selective historical review of important discoveries that have shaped our understanding of immune dysfunction in SSD. We first explain the basic principles of immune dysfunction, after which we travel more than a century back in time. Starting our journey with neurosyphilis-associated psychosis in the nineteenth century, we continue by evaluating the role of infections and autoimmunity in SSD and findings from assessment of immune function using new techniques, such as cytokine levels, microglia density, neuroimaging, and gene expression. Drawing from these findings, we discuss anti-inflammatory interventions for SSD, and we conclude with a look into the future.

The degree of physiological responses to individual antipsychotic drugs is unclear in children and adolescents. With network meta-analysis, we aimed to investigate the effects of various antipsychotic medications on physiological variables in children and adolescents with neuropsychiatric and neurodevelopmental conditions.

For this network meta-analysis, we searched Medline, EMBASE, PsycINFO, Web of Science, and Scopus from database inception until Dec 22, 2023, and included randomised controlled trials comparing antipsychotics with placebo in children or adolescents younger than 18 years with any neuropsychiatric and neurodevelopmental condition. Primary outcomes were mean change from baseline to end of acute treatment in bodyweight, BMI, fasting glucose, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, prolactin, heart rate, systolic blood pressure (SBP), and QT interval corrected for heart rate (QTc) for patients receiving either active treatment or placebo. For multigroup trials reporting several doses, we calculated a summary value for each physiological variable for all doses. After transitivity assessment, we fitted frequentist random-effects network meta-analyses for all comparisons in the network. A Kilim plot was used to summarise the results for all treatments and outcomes, providing information regarding the strength of the statistical evidence of treatment effects, using p values. Network heterogeneity was assessed with τ, risk of bias of individual trials was assessed with the Cochrane Collaboration's Tool for Assessing Risk of Bias, and the credibility of findings from each network meta-analysis was assessed with the Confidence in Network Meta-Analysis (CINEMA) app. This study is registered on PROSPERO (CRD42021274393).

Of 6676 studies screened, 47 randomised controlled trials were included, which included 6500 children (mean age 13·29 years, SD 2·14) who received treatment for a median of 7 weeks (IQR 6-8) with either placebo (n=2134) or one of aripiprazole, asenapine, blonanserin, clozapine, haloperidol, lurasidone, molindone, olanzapine, paliperidone, pimozide, quetiapine, risperidone, or ziprasidone (n=4366). Mean differences for bodyweight change gain compared with placebo ranged from -2·00 kg (95% CI -3·61 to -0·39) with molindone to 5·60 kg (0·27 to 10·94) with haloperidol; BMI -0·70 kg/m2 (-1·21 to -0·19) with molindone to 2·03 kg/m2 (0·51 to 3·55) with quetiapine; total cholesterol -0·04 mmol/L (-0·39 to 0·31) with blonanserin to 0·35 mmol/L (0·17 to 0·53) with quetiapine; LDL cholesterol -0·12 mmol/L (-0·31 to 0·07) with risperidone or paliperidone to 0·17 mmol/L (-0·06 to 0·40) with olanzapine; HDL cholesterol 0·05 mmol/L (-0·19 to 0·30) with quetiapine to 0·48 mmol/L (0·18 to 0·78) with risperidone or paliperidone; triglycerides -0·03 mmol/L (-0·12 to 0·06) with lurasidone to 0·29 mmol/L (0·14 to 0·44) with olanzapine; fasting glucose from -0·09 mmol/L (-1·45 to 1·28) with blonanserin to 0·74 mmol/L (0·04 to 1·43) with quetiapine; prolactin from -2·83 ng/mL (-8·42 to 2·75) with aripiprazole to 26·40 ng/mL (21·13 to 31·67) with risperidone or paliperidone; heart rate from -0·20 bpm (-8·11 to 7·71) with ziprasidone to 12·42 bpm (3·83 to 21·01) with quetiapine; SBP from -3·40 mm Hg (-6·25 to -0·55) with ziprasidone to 10·04 mm Hg (5·56 to 14·51) with quetiapine; QTc from -0·61 ms (-1·47 to 0·26) with pimozide to 0·30 ms (-0·05 to 0·65) with ziprasidone.

Children and adolescents show varied but clinically significant physiological responses to individual antipsychotic drugs. Treatment guidelines for children and adolescents with a range of neuropsychiatric and neurodevelopmental conditions should be updated to reflect each antipsychotic drug's distinct profile for associated metabolic changes, alterations in prolactin, and haemodynamic alterations.

UK Academy of Medical Sciences, Brain and Behaviour Research Foundation, UK National Institute of Health Research, Maudsley Charity, the Wellcome Trust, Medical Research Council, National Institute of Health and Care Research Biomedical Centre at King's College London and South London and Maudsley NHS Foundation Trust, the Italian Ministry of University and Research, the Italian National Recovery and Resilience Plan, and Swiss National Science Foundation.