Treatment Of Schizophrenia Research Articles

Mechanism of electroconvulsive therapy in schizophrenia: a bioinformatics analysis study of RNA-seq data.

The molecular mechanism of electroconvulsive therapy (ECT) for schizophrenia remains unclear. The aim of this study was to uncover the underlying biological mechanisms of ECT in the treatment of schizophrenia using a transcriptional dataset. The peripheral blood mRNA sequencing data of eight patients (before and after ECT) and eight healthy controls were analyzed by integrated co-expression network analysis and the differentially expressed genes were analyzed by cluster analysis. Gene set overlap analysis was performed using the hypergeometric distribution of phypfunction in R. Associations of these gene sets with psychiatric disorders were explored. Tissue-specific enrichment analysis, gene ontology enrichment analysis, and protein-protein interaction enrichment analysis were used for gene set organization localization and pathway analysis. We found the genes of the green-yellow module were significantly associated with the effect of ECT treatment and the common gene variants of schizophrenia ( P = 0.0061; family-wise error correction). The genes of the green-yellow module are mainly enriched in brain tissue and mainly involved in the pathways of neurotrophin, mitogen-activated protein kinase and long-term potentiation. Genes associated with the efficacy of ECT were predominantly enriched in neurotrophin, mitogen-activated protein kinase and long-term potentiation signaling pathways.

Transport mechanism and pharmacology of the human GlyT1

The glycine transporter 1 (GlyT1) plays a crucial role in the regulation of both inhibitory and excitatory neurotransmission by removing glycine from the synaptic cleft. Given its close association with glutamate/glycine co-activated NMDA receptors (NMDARs), GlyT1 has emerged as a central target for the treatment of schizophrenia, which is often linked to hypofunctional NMDARs. Here, we report the cryo-EM structures of GlyT1 bound with substrate glycine and drugs ALX-5407, SSR504734, and PF-03463275. These structures, captured at three fundamental states of the transport cycle-outward-facing, occluded, and inward-facing-enable us to illustrate a comprehensive blueprint of the conformational change associated with glycine reuptake. Additionally, we identified three specific pockets accommodating drugs, providing clear insights into the structural basis of their inhibitory mechanism and selectivity. Collectively, these structures offer significant insights into the transport mechanism and recognition of substrate and anti-schizophrenia drugs, thus providing a platform to design small molecules to treat schizophrenia.

New, not anti-dopaminergic antipsychotic drugs in the treatment of schizophrenia, M4 or M1 receptor agonists and TAAR1 agonists

New, not anti-dopaminergic antipsychotic drugs in the treatment of schizophrenia, M4 or M1 receptor agonists and TAAR1 agonists

The Pathogenesis and Remedial Treatment (and Management) of Schizophrenia

The pathogenesis of schizophrenia has been understood to commence with the intense painfulness of the young person’s early environments, as their representational world. This preconscious representation of their early environments can be experienced so adversely as to impinge on brain function, namely the level of the individual’s wellbeing as evaluated by the nucleus accumbens, which also evaluates wellbeing as a rewarding consequence of exposure to drugs of addiction. Involving connection with the A10 nucleus, which is arguably homeostatic like the homeostatic nuclei that surround it in the brainstem, the nucleus accumbens and prefrontal cortex secrete excessive amounts of dopamine to counteract the individual’s dysphoria. This adversely affects the functioning of the prefrontal cortex, which leads to the common manifestations of schizophrenia. Successful treatment is directly aligned with its proposed pathogenesis. Palliative management can provide alleviation to a lesser extent of some aspects of the illness.

Structure-Based Design of Novel G-Protein-Coupled Receptor TAAR1 Agonists as Potential Antipsychotic Drug Candidates.

The existing available antipsychotics have failed to manage the cognitive impairment of schizophrenia and induced a number of seriously undesirable effects. Trace amine-associated receptor 1 (TAAR1) has emerged as an ideal target for the design of antischizophrenia drugs, with the ability to mediate multiple psychological functions by sensing endogenous amine-containing metabolites without the side effects of catalepsy. In this work, a series of novel TAAR1 agonists were designed based on the structural analysis of the TAAR1 activation pocket. Among them, 6e displayed a potent TAAR1-Gs/Gq dual-pathway activation property, being different from that of the clinical drug candidate SEP-363856 with only TAAR1-Gs pathway activation. In rodent models, 6e significantly alleviated MK-801-induced schizophrenia-like cognitive phenotypes without inducing catalepsy. Furthermore, 6e·HCl exhibited favorable pharmacokinetic (T1/2 = 2.31 h, F = 39%) and safety properties. All these demonstrated that 6e·HCl may be used as a novel drug candidate for schizophrenia treatment.

Potential Analysis of Drug Interactions in Schizophrenia Cases At One of the Bandung District Pharmacy, Indonesia

Schizophrenia is a heterogeneous syndrome of thought disturbances, delusions, hallucinations, emotional disturbances, decreased cognitive function and disturbed psychosocial functions. Treatment of schizophrenia aims to prevent hospitalization, ensure the patient's symptoms are stable and independent such as work or school. The purpose of this study was to determine the potential for drug interactions in schizophrenia cases based on their mechanism of action and severity. This research method is a descriptive study using data collected retrospectively on prescription drug data sheets in the pharmacy. The collected data were analyzed quantitatively and qualitatively. The results of the study from a total of 133 prescriptions found potential drug interactions in 509 cases. Drug interactions based on the mechanism of action, pharmacodynamics were found in 494 cases and 15 cases of pharmacokinetic . Based on the level of severity, there were interactions with 15 cases of mild severity, 287 cases of moderate severity and 217 cases of severe severity

Formulation Development of Solid Self-Nanoemulsifying Drug Delivery Systems of Quetiapine Fumarate via Hot-Melt Extrusion Technology: Optimization Using Central Composite Design.

Quetiapine fumarate (QTF) was approved for the treatment of schizophrenia and acute manic episodes. QTF can also be used as an adjunctive treatment for major depressive disorders. QTF oral bioavailability is limited due to its poor aqueous solubility and pre-systemic metabolism. The objective of the current investigation was the formulation development and manufacturing of solid self-nanoemulsifying drug delivery system (S-SNEDDS) formulation through a single-step continuous hot-melt extrusion (HME) process to address these drawbacks. In this study, Capmul® MCM, Gelucire® 48/16, and propylene glycol were selected as oil, surfactant, and co-surfactant, respectively, for the preparation of S-SNEDDS. Soluplus® and Klucel™ EF (1:1) were selected as the solid carrier. Response surface methodology in the form of central composite design (CCD) was utilized in the current experimental design to develop the S-SNEDDS formulations via a continuous HME technology. The developed formulations were evaluated for self-emulsifying properties, particle size distribution, thermal behavior, crystallinity, morphology, physicochemical incompatibility, accelerated stability, and in vitro drug release studies. The globule size and emulsification time of the optimized SNEDDS formulation was 92.27 ± 3.4 nm and 3.4 ± 3.38 min. The differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies revealed the amorphous nature of the drug within the formulation. There were no drug-excipient incompatibilities observed following the Fourier transform infrared (FTIR) spectroscopy. The optimized formulation showed an extended-release profile for 24 h. The optimized formulation was stable for three months (last time-point tested) at 40 °C/75% RH. Therefore, the developed S-SNEDDS formulation could be an effective oral delivery platform for QTF and could lead to better therapeutic outcomes.

Trajectories and predictors of response to social cognition training in people with schizophrenia: A proof-of-concept machine learning study

BackgroundSocial cognition training (SCT) can improve social cognition deficits in schizophrenia. However, little is known about patterns of response to SCT or individual characteristics that predict response. Methods76 adults with schizophrenia randomized to receive 8–12 weeks of remotely-delivered SCT were included in this analysis. Social cognition was measured with a composite of six assessments. Latent class growth analyses identified trajectories of social cognitive response to SCT. Random forest and logistic regression models were trained to predict membership in the trajectory group that showed improvement from baseline measures including symptoms, functioning, motivation, and cognition. ResultsFive trajectory groups were identified: Group 1 (29 %) began with slightly above average social cognition, and this ability significantly improved with SCT. Group 2 (9 %) had baseline social cognition approximately one standard deviation above the sample mean and did not improve with training. Groups 3 (18 %) and 4 (36 %) began with average to slightly below-average social cognition and showed non-significant trends toward improvement. Group 5 (8 %) began with social cognition approximately one standard deviation below the sample mean, and experienced significant deterioration in social cognition. The random forest model had the best performance, predicting Group 1 membership with an area under the curve of 0.73 (SD 0.24; 95 % CI [0.51–0.87]). ConclusionsFindings suggest that there are distinct patterns of response to SCT in schizophrenia and that those with slightly above average social cognition at baseline may be most likely to experience gains. Results may inform future research seeking to individualize SCT treatment for schizophrenia.

Peripheral Blood Non-Coding RNA as Biomarker for Schizophrenia: A Review.

Schizophrenia (SCZ) is a complex and heterogeneous neuropsychiatric disorder that lacks objective diagnostic indicators and the pathogenesis remain unclear. Genetic factors may exert a significant impact on the development of the condition. While obtaining brain tissue for biopsy in the course of adjuvant diagnosis of SCZ patients may not be possible, the collection of peripheral blood is more accessible and easier to implement. In recent years, the development and application of RNA sequencing technology has made seeking biomarkers of SCZ becomes more feasible. There is emerging evidence suggesting that certain non-coding RNAs (ncRNA) are distinctly different in the peripheral blood of SCZ patients and healthy controls. Although the mechanisms remain unclear, these aberrantly expressed ncRNAs may be intimately associated with the onset and development of SCZ and may be of great significance for the diagnosis and treatment of SCZ. Therefore, we reviewed the expression of distinct types of ncRNAs that have been found in the peripheral blood of SCZ patients and explored their potential application as diagnostic biomarkers of SCZ. Differentially expressed ncRNAs in the peripheral blood of SCZ patients could not only serve as potential diagnostic biomarkers and therapeutic targets for SCZ but may also have implications for advancing understanding of the molecular mechanisms underlying the development of SCZ and elucidating the complex etiology of SCZ. Early diagnostic biomarkers obtained directly from peripheral blood are of great significance for the timely diagnosis and treatment of SCZ. Our review will enhance the comprehension of molecular mechanisms of SCZ and contribute to the identification of promising ncRNAs in peripheral blood for both diagnosis and therapy of SCZ.

Modulation of neuronal morphology by antipsychotic drug: Involvement of serotonin receptor 7

Antipsychotic drugs (APDs) are the primary pharmacological treatment for schizophrenia, a complex disorder characterized by altered neuronal connectivity. Atypical or second-generation antipsychotics, such as Risperidone (RSP) and Clozapine (CZP) predominantly block dopaminergic D2 and serotonin receptor 2A (5-HT2A) neurotransmission. Both compounds also exhibit affinity for the 5-HT7R, with RSP acting as an antagonist and CZP as an inverse agonist. Our study aimed to determine whether RSP and CZP can influence neuronal morphology through a 5-HT7R-mediated mechanism. Here, we demonstrated that CZP promotes neurite outgrowth of early postnatal cortical neurons, and the 5-HT7R mediates its effect. Conversely, RSP leads to a reduction of neurite length of early postnatal cortical neurons, in a 5-HT7R-independent way.Furthermore, we found that the effects of CZP, mediated by 5-HT7R activation, require the participation of ERK and Cdk5 kinase pathways. At the same time, the modulation of neurite length by RSP does not involve these pathways.In conclusion, our findings provide valuable insights into the morphological changes induced by these two APDs in neurons and elucidate some of the associated molecular pathways. Investigating the 5-HT7R-dependent signaling pathways underlying the neuronal morphogenic effects of APDs may contribute to the identification of novel targets for the treatment of schizophrenia.

A woman with schizophrenia who died due to Takotsubo cardiomyopathy occurring after electroconvulsive therapy

BackgroundElectroconvulsive therapy (ECT) is a safe treatment for treatment-resistant schizophrenia. However, it has some side effects, and Takotsubo cardiomyopathy is considered one of the minor complications. Several cases of patients developing Takotsubo cardiomyopathy during a course of ECT have been reported, but none have died. We present a case of post-ECT Takotsubo cardiomyopathy that became fatal.Case presentationWe experienced a case of a 67-year-old woman who had delusions and catatonic symptoms due to schizophrenia but was resistant to several medications. Her symptoms improved by conducting ECT, but she had difficulty maintaining her improvement, which caused her to receive multiple courses of ECT. 3 weeks after her 6th course of ECT, the patient was diagnosed with Takotsubo cardiomyopathy and had a fatal outcome.ConclusionOur patient had numerous cases of aspiration pneumonia and malnutrition before ECT was performed, which might have made this case fatal. In conclusion, appropriate supplementation of nutrition and reduction of physical stressors are important to avoid death from Takotsubo cardiomyopathy caused by ECT. Prescribing clozapine was a solution in the present case, but there are some difficulties, such as the restriction against prescribing this drug in Japan.

Exploring peripheral biomarkers of response to simvastatin supplementation in schizophrenia

Schizophrenia is one of the most debilitating mental disorders, and its diagnosis and treatment present significant challenges. Several clinical trials have previously evaluated the effectiveness of simvastatin, a lipid-lowering medication, as a novel add-on treatment for schizophrenia. However, treatment effects varied highly between patients and over time. In the present study, we aimed to identify biomarkers of response to simvastatin in recent-onset schizophrenia patients. To this end, we profiled relevant immune and metabolic markers in patient blood samples collected in a previous clinical trial (ClinicalTrials.gov: NCT01999309) before simvastatin add-on treatment was initiated. Analysed sample types included serum, plasma, resting-state peripheral blood mononuclear cells (PBMCs), as well as PBMC samples treated ex vivo with immune stimulants and simvastatin. Associations between the blood readouts and clinical endpoints were evaluated using multivariable linear regression. This revealed that changes in insulin receptor (IR) levels induced in B-cells by ex vivo simvastatin treatment inversely correlated with in vivo effects on cognition at the primary endpoint of 12 months, as measured using the Brief Assessment of Cognition in Schizophrenia scale total score (standardised β ± SE = −0.75 ± 0.16, P = 2.2 × 10−4, Q = 0.029; n = 21 patients). This correlation was not observed in the placebo group (β ± SE = 0.62 ± 0.39, P = 0.17, Q = 0.49; n = 14 patients). The candidate biomarker explained 53.4 % of the variation in cognitive outcomes after simvastatin supplementation. Despite the small sample size, these findings suggest a possible interaction between the insulin signalling pathway and cognitive effects during simvastatin therapy. They also point to opportunities for personalized schizophrenia treatment through patient stratification.

Genetic prediction of the causal relationship between schizophrenia and tumors: a Mendelian randomized study.

Patients with schizophrenia are at a higher risk of developing cancer. However, the causal relationship between schizophrenia and different tumor types remains unclear. Using a two-sample, two-way Mendelian randomization method, we used publicly available genome-wide association analysis (GWAS) aggregate data to study the causal relationship between schizophrenia and different cancer risk factors. These tumors included lung adenocarcinoma, lung squamous cell carcinoma, small-cell lung cancer, gastric cancer, alcohol-related hepatocellular cancer, tumors involving the lungs, breast, thyroid gland, pancreas, prostate, ovaries and cervix, endometrium, colon and colorectum, and bladder. We used the inverse variance weighting (IVW) method to determine the causal relationship between schizophrenia and different tumor risk factors. In addition, we conducted a sensitivity test to evaluate the effectiveness of the causality. After adjusting for heterogeneity, evidence of a causal relationship between schizophrenia and lung cancer risk was observed (odds ratio [OR]=1.001, 95% confidence interval [CI], 1.000-1.001; P=0.0155). In the sensitivity analysis, the causal effect of schizophrenia on the risk of lung cancer was consistent in both direction and degree. However, no evidence of causality or reverse causality between schizophrenia and other tumors was found. This study elucidated a causal relationship between the genetic predictors of schizophrenia and the risk of lung cancer, thereby providing a basis for the prevention, pathogenesis, and treatment of schizophrenia in patients with lung cancer.

CLEAR – clozapine in early psychosis: study protocol for a multi-centre, randomised controlled trial of clozapine vs other antipsychotics for young people with treatment resistant schizophrenia in real world settings

BackgroundClozapine is an antipsychotic drug with unique efficacy, and it is the only recommended treatment for treatment-resistant schizophrenia (TRS: failure to respond to at least two different antipsychotics). However, clozapine is also associated with a range of adverse effects which restrict its use, including blood dyscrasias, for which haematological monitoring is required. As treatment resistance is recognised earlier in the illness, the question of whether clozapine should be prescribed in children and young people is increasingly important. However, most research to date has been in older, chronic patients, and evidence regarding the efficacy and safety of clozapine in people under age 25 is lacking. The CLEAR (CLozapine in EARly psychosis) trial will assess whether clozapine is more effective than treatment as usual (TAU), at the level of clinical symptoms, patient rated outcomes, quality of life and cost-effectiveness in people below 25 years of age. Additionally, a nested biomarker study will investigate the mechanisms of action of clozapine compared to TAU.Methods and designThis is the protocol of a multi-centre, open label, blind-rated, randomised controlled effectiveness trial of clozapine vs TAU (any other oral antipsychotic monotherapy licenced in the British National Formulary) for 12 weeks in 260 children and young people with TRS (12–24 years old).Aim and objectivesThe primary outcome is the change in blind-rated Positive and Negative Syndrome Scale scores at 12 weeks from baseline. Secondary outcomes include blind-rated Clinical Global Impression, patient-rated outcomes, quality of life, adverse effects, and treatment adherence. Patients will be followed up for 12 months and will be invited to give consent for longer term follow-up using clinical records and potential re-contact for further research. For mechanism of action, change in brain magnetic resonance imaging (MRI) biomarkers and peripheral inflammatory markers will be measured over 12 weeks.DiscussionThe CLEAR trial will contribute knowledge on clozapine effectiveness, safety and cost-effectiveness compared to standard antipsychotics in young people with TRS, and the results may guide future clinical treatment recommendation for early psychosis.Trial registrationISRCTN Number: 37176025, IRAS Number: 1004947.Trial statusIn set-up. Protocol version 4.0 01/08/23. Current up to date protocol available here: https://fundingawards.nihr.ac.uk/award/NIHR131175#/.

Autophagy-related gene model as a novel risk factor for schizophrenia

Autophagy, a cellular process where cells degrade and recycle their own components, has garnered attention for its potential role in psychiatric disorders, including schizophrenia (SCZ). This study aimed to construct and validate a new autophagy-related gene (ARG) risk model for SCZ. First, we analyzed differential expressions in the GSE38484 training set, identifying 4,754 differentially expressed genes (DEGs) between SCZ and control groups. Using the Human Autophagy Database (HADb) database, we cataloged 232 ARGs and pinpointed 80 autophagy-related DEGs (AR-DEGs) after intersecting them with DEGs. Subsequent analyses, including metascape gene annotation, pathway and process enrichment, and protein-protein interaction enrichment, were performed on the 80 AR-DEGs to delve deeper into their biological roles and associated molecular pathways. From this, we identified 34 candidate risk AR-DEGs (RAR-DEGs) and honed this list to final RAR-DEGs via a constructed and optimized logistic regression model. These genes include VAMP7, PTEN, WIPI2, PARP1, DNAJB9, SH3GLB1, ATF4, EIF4G1, EGFR, CDKN1A, CFLAR, FAS, BCL2L1 and BNIP3. Using these findings, we crafted a nomogram to predict SCZ risk for individual samples. In summary, our study offers deeper insights into SCZ’s molecular pathogenesis and paves the way for innovative approaches in risk prediction, gene-targeted diagnosis, and community-based SCZ treatments.

Current advances in pharmacotherapy for schizophrenia

Background: Schizophrenia is a complex psychiatric disorder characterized by hallucinations, delusions, and cognitive deficits, often leading to functional decline. Pharmacotherapy has long played a central role in schizophrenia management with our evolving understanding shaping the treatment.Current Concepts: Antipsychotic agents are the mainstay of the pharmacological treatment of schizophrenia. Although second-generation antipsychotics (atypical) reduce extrapyramidal side effects, they give rise to metabolic concerns. Personalized treatment, guided by the response and side effects of the patient, determines suitable medications and dosages. Long-acting injectable antipsychotics have enhanced medication adherence, and the consideration of clozapine is warranted for treatment-resistant cases. In addition, potential combination therapies with other psychotropic medications could be explored to address specific symptoms or comorbidities.Discussion and Conclusion: Antipsychotics are pivotal in acute intervention and schizophrenia treatment maintenance. Individualized plans, accounting for drug response, side effects, and adherence, are essential when selecting specific antipsychotic agents. Long-acting injectables and clozapine with combination therapies for treatment resistance offer effective and tolerable management. Ongoing studies and novel antipsychotic development hold promise for improving schizophrenia treatment and patient life quality.

Analisis Kejadian Interaksi Obat pada Pasien Skizofrenia di RSUD Dr. Iskak Tulungagung

Schizophrenia is a syndrome with multiple ethology, outcome differ depending on the chronic course of the diseases, and the balance of physical, genetic also influences in the country. Schizophrenia patients have psychotic symptoms, so the main psychopharmacology given to schizophrenia patients is antipsychotics. The main treatment for schizophrenia is antipsychotic drugs, many schizophrenia patients receive combination therapy with antipsychotic drugs. Drug interactions generally refer to changes in drug response resulting from a patient's exposure to a drug or other substance. The potential severity of interactions is important for evaluating the risks and benefits of alternative treatments. Severity is classified into mild severity (effects are usually mild), moderate severity (new effects may cause severity of the patient's disease), and severe severity (possibly life-threatening or may cause permanent damage). This study aims to determine drug interactions and treatment patterns regarding pharmacokinetic and pharmacodynamics interactions in schizophrenia patients at Iskak Tulungagung Hospital. The research method uses analytics with retrospective data collection. The research sample consisted of 48 respondents in the categories mild (2%), moderate (78%), and severe (20%). The results display is potential for drug interactions in the form of pharmacodynamics potential (97%) which dominates more than pharmacokinetic potential (3%).

Psychosocial and digital intervention for patients with schizophrenia

Background: Schizophrenia is a severe mental disorder that significantly impairs the daily functioning of patients that causes substantial societal and economic burden. While drug therapy is crucial for schizophrenia treatment, relying solely on antipsychotic drugs does not yield the most favorable therapeutic outcomes.Current Concepts: Integrating psychosocial interventions could result in maximized therapeutic effects for individuals living with schizophrenia. Evidence-based psychosocial interventions for schizophrenia management include cognitive behavioral therapy, family involvement, psychoeducation, supported employment programs, lifestyle adjustments for physical health, and coordinated and comprehensive early intervention services. Incorporating peer support, allowing both service users and care providers to share knowledge and their illnessrelated personal experiences, facilitates mutual assistance along the path to recovery. Moreover, growing interest follows in using digital interventions, such as wearable technology and smartphone applications, as effective therapeutic tools for illness management.Discussion and Conclusion: The above-mentioned psychosocial interventions empower individuals with schizophrenia, helping them improve their functioning, enhance their life quality, and adapt more effectively to society. Combining early medication with comprehensive psychosocial interventions, including digital technology, is crucial for the best outcomes. This approach should begin as soon as schizophrenia is diagnosed, aiming to promote recovery and overall well-being in affected individuals.

Genome-wide association study implicates lipid pathway dysfunction in antipsychotic-induced weight gain: multi-ancestry validation.

Antipsychotic-induced weight gain (AIWG) is a common side effect of antipsychotic medication and may contribute to diabetes and coronary heart disease. To expand the unclear genetic mechanism underlying AIWG, we conducted a two-stage genome-wide association study in Han Chinese patients with schizophrenia. The study included a discovery cohort of 1936 patients and a validation cohort of 534 patients, with an additional 630 multi-ancestry patients from the CATIE study for external validation. We applied Mendelian randomization (MR) analysis to investigate the relationship between AIWG and antipsychotic-induced lipid changes. Our results identified two novel genome-wide significant loci associated with AIWG: rs10422861 in PEPD (P = 1.373 × 10-9) and rs3824417 in PTPRD (P = 3.348 × 10-9) in Chinese Han samples. The association of rs10422861 was validated in the European samples. Fine-mapping and functional annotation revealed that PEPD and PTPRD are potentially causal genes for AIWG, with their proteins being prospective therapeutic targets. Colocalization analysis suggested that AIWG and type 2 diabetes (T2D) shared a causal variant in PEPD. Polygenic risk scores (PRSs) for AIWG and T2D significantly predicted AIWG in multi-ancestry samples. Furthermore, MR revealed a risky causal effect of genetically predicted changes in low-density lipoprotein cholesterol (P = 7.58 × 10-4) and triglycerides (P = 2.06 × 10-3) caused by acute-phase of antipsychotic treatment on AIWG, which had not been previously reported. Our model, incorporating antipsychotic-induced lipid changes, PRSs, and clinical predictors, significantly predicted BMI percentage change after 6-month antipsychotic treatment (AUC = 0.79, R2 = 0.332). Our results highlight that the mechanism of AIWG involves lipid pathway dysfunction and may share a genetic basis with T2D through PEPD. Overall, this study provides new insights into the pathogenesis of AIWG and contributes to personalized treatment of schizophrenia.

Precision medicine for psychotic disorders: objective assessment, risk prediction, and pharmacogenomics.

Psychosis occurs inside the brain, but may have external manifestations (peripheral molecular biomarkers, behaviors) that can be objectively and quantitatively measured. Blood biomarkers that track core psychotic manifestations such as hallucinations and delusions could provide a window into the biology of psychosis, as well as help with diagnosis and treatment. We endeavored to identify objective blood gene expression biomarkers for hallucinations and delusions, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We were successful in identifying biomarkers that were predictive of high hallucinations and of high delusions states, and of future psychiatric hospitalizations related to them, more so when personalized by gender and diagnosis. Top biomarkers for hallucinations that survived discovery, prioritization, validation and testing include PPP3CB, DLG1, ENPP2, ZEB2, and RTN4. Top biomarkers for delusions include AUTS2, MACROD2, NR4A2, PDE4D, PDP1, and RORA. The top biological pathways uncovered by our work are glutamatergic synapse for hallucinations, as well as Rap1 signaling for delusions. Some of the biomarkers are targets of existing drugs, of potential utility in pharmacogenomics approaches (matching patients to medications, monitoring response to treatment). The top biomarkers gene expression signatures through bioinformatic analyses suggested a prioritization of existing medications such as clozapine and risperidone, as well as of lithium, fluoxetine, valproate, and the nutraceuticals omega-3 fatty acids and magnesium. Finally, we provide an example of how a personalized laboratory report for doctors would look. Overall, our work provides advances for the improved diagnosis and treatment for schizophrenia and other psychotic disorders.