Prediction of treatment response to antipsychotic drugs for precision medicine approach to schizophrenia:randomized trials and multiomics analysis

Background:Choosing the appropriate antipsychotic drug(APD)treatment for patients with schizophrenia(SCZ)can be challenging,as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers.Previous studies have indicated the association between treatment response and genetic and epigenetic factors,but no effective biomarkers have been identified.Hence,further research is imperative to enhance precision medicine in SCZ treatment.Methods:Participants with SCZ were recruited from two randomized trials.The discovery cohort was recruited from the CAPOC trial(n=2307)involved 6 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,Quetiapine,Aripiprazole,Ziprasidone,and Haloperidol/Perphenazine(subsequently equally assigned to one or the other)groups.The external validation cohort was recruited from the CAPEC trial(n=1379),which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,and Aripiprazole groups.Additionally,healthy controls(n=275)from the local community were utilized as a genetic/epigenetic reference.The genetic and epigenetic(DNA methylation)risks of SCZ were assessed using the polygenic risk score(PRS)and polymethylation score,respectively.The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis,methylation quantitative trait loci,colocalization,and promoteranchored chromatin interaction.Machine learning was used to develop a prediction model for treatment response,which was evaluated for accuracy and clinical benefit using the area under curve(AUC)for classification,R^(2) for regression,and decision curve analysis.Results:Six risk genes for SCZ(LINC01795,DDHD2,SBNO1,KCNG2,SEMA7A,and RUFY1)involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response.The developed and externally validated prediction model,which incorporated clinical information,PRS,genetic risk score(GRS),and proxy methylation level(proxyDNAm),demonstrated positive benefits for a wide range of patients receiving different APDs,regardless of sex[discovery cohort:AUC=0.874(95%CI 0.867-0.881),R^(2)=0.478;external validation cohort:AUC=0.851(95%CI 0.841-0.861),R^(2)=0.507].Conclusions:This study presents a promising precision medicine approach to evaluate treatment response,which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ.Trial registration Chinese Clinical Trial Registry(https://www.chictr.org.cn/),18 Aug 2009 retrospectively registered:CAPOC-ChiCTR-RNC-09000521(https://www.chictr.org.cn/showproj.aspx?proj=9014),CAPEC-ChiCTRRNC-09000522(https://www.chictr.org.cn/showproj.aspx?proj=9013).

Aging effects on QT interval： Implications for cardiac safety of antipsychotic drugs

Objectives To explore the effect of aging on cardiac toxicity specifically the interaction of age and antipsychotic drugs to alter the QT interval. Methods The Medline databases were searched using the OvidSP platforms with the search strategy： ＂QT interval＂ or ＂QT＂ and ＂age＂ or ＂aging＂. The entry criteria were： over 10,000 apparently healthy individuals with data on both sexes; QT interval corrected for heart rate （QTc） and an expression of its variance for multiple age decades extending into the older ages. Results QTc increased in duration with increasing age. Considering a modest one SD increment in QTc in the normal population, the addition of Chlorpromazine produced a QTc on average greater than 450 ms for ages 70 years and older. Risperidone, that did not on average alter QTc, would be expected to produce a QTc of 450 ms in persons in their mid 70 years under some circumstances. QTc prolongation 〉 500 ms with antipsychotic drugs is more likely for persons with QTc initially at the 99th percentile. It may occur with Haloperidol which does not on average alter QTc. Conclusions The range of values for the QT interval in apparently normal older men or women, when combined with the range of expected QT interval changes induced by antipsychotic drugs, can readily be associated with prolonged QTc. Individuals with QTc at the 99th percentile may have serious QTc prolongation with antipsychotic drugs even those that are not usually associated with QTc prolongation.

Classical Neurotransmitters and Neuropeptides Involved in Schizophrenia： How to Improve the Therapeutic Effect of the Antipsychotic Drugs

We describe the alterations of classical neurotransmitters and neuropeptides in schizophrenia. In this disease, susceptibility genes encode GABA （gamma-aminobutyric acid） and glutamate hypofunction and dopamine hyperactivity. A neural network is developed in the mesolimbic system, the hippocampus and the prefrontal cortex. According to this neural network, dopamine and serotonin hyperactivity might be due to a reduced presynaptic inhibition through GABAergic and glutaminergic neurons. A survey of the therapeutic and adverse effects of commonly prescribed and of recently developed second-generation antipsychotic drugs is given The interaction with other specific subreceptors of classical neurotransmitters and neuropeptides is suggested to improve the antipsychotic effect. In the treatment of schizophrenia, pharmacotherapy should be combined with psychoeducation. Accordingly, a recurrence of psychotic symptoms could be prevented in a long-term treatment.

Interaction of antipsychotic drug with novel surfactants: Micellization and binding studies

The interaction of cationic gemini surfactants(alkanediyl-α,ω-bis(alkyl dimethylammonium bromide)) with an antipsychotic drug(chlorpromazine hydrochloride(CPZ)) has been investigated. Various micellar and interfacial parameters have been deliberated by surface tension measurement to report the nature of interactions between drug and novel surfactant mixtures. The behavior of mixed systems, their compositions and activities of components have been analyzed in the light of Rubingh's theory. The results indicate synergism in the binary mixtures.The binding study between CPZ and surfactants has been done by spectroscopic techniques such as UV–visible and fluorescence. The results are discussed in the light of the use of gemini surfactants as promising drug delivery agents for phenothiazine drugs, and hence, improve their bioavailability.

The Effect of Several Commonly Used Antipsychotic Drugs on the Renal Function of Patients with Mental Illness

Objective: To understand the effects of several commonly used antipsychotics on the renal function of patients with mental illness. Method: Collected patients with mental illness who were hospitalized in our hospital from January 2020 to June 2021, and selected as the research subjects patients with psychiatric disorders who were treated with 2 kinds of commonly used antipsychotic drugs;and collected 3 ml of venous blood before treatment and one month after treatment for renal function tests;observed the changes of renal function indexes before and after treatment. Results: In the collected 694 patients with mental illness, before using antipsychotic drugs, the renal function indexes were BUN: 4.42 ± 1.92 mmol/l;Cr: 70.97 ± 16.92 μmol/l;CCr: 88.37 ± 21.07 ml/min;β2-MG: 1.67 ± 0.61 mg/L;UA: 359.90 ± 112.82 μmol/l;CYS-C: 0.92 ± 0.24 mg/L. One month after using antipsychotics, BUN: 3.77 ± 1.37 mmol/l;Cr: 70.46 ± 16.71 μmol/l;CCr: 87.78 ± 20.63 ml/min;β2-MG: 1.75 ± 0.64 mg/L;UA: 332.53 ± 91.48 umol/l;CYS-C: 0.92 ± 0.24 mg/L;the renal function indexes of urea nitrogen, β2 microglobulin, uric acid and other items all changed significantly. The differences before and after treatment were statistically significant, P < 0.01. Conclusion: Several commonly used antipsychotic drugs have a greater impact on the renal function of patients with mental illness. During the treatment, the changes in renal function should be monitored regularly, if severe renal damage is found, the treatment plan or dosage should be adjusted in time to avoid endangering life.

Bias in multiple-treatments meta-analysis： a case on comparative efficacy and tolerability of 15 antipsychotic drugs for schizophrenia

Multiple-treatments meta-analysis is thought to be a feasible method to compare the efficacy and safety among different treatments, especially when there was no head-to-head research among some treatments. But sometimes some conclusions are inconsistent with the clinical experience. Recently, we read a multiple-treatment meta-analysis finished by Stefen Leucht et al, which was published in Lancet） The authors summarized the results of the RCT studies on 15 antipsychotics commonly used in practice; they also horizontally compared the efficacy and safety profile by the recta-analysis. We believe that the results provide more solid evidence for the rational usage of antipsychotics to the psychiatrists, also for the government to distribute health resources in a more reasonable way.

Antipsychotic drug research and resting-state brain activity in normal adults

In the field of functional MRI,compared to observations of task-related brain activity,a growing number of studies have shown that spontaneous brain activity during the resting state may be more sensitive to defects in the cognitive functions of our brain.

Trajectories of response in schizophrenia-spectrum disorders: A one-year prospective cohort study of antipsychotic effectiveness

BACKGROUND Antipsychotic drugs remain the mainstay of schizophrenia treatment;however,their effectiveness has been questioned,and it is not possible to predict the response to a specific antipsychotic drug in an individual patient.Thus,it is important to compare the effectiveness of the various antipsychotics and search for possible response predictors.AIM To investigate the effectiveness of antipsychotic drugs,we examined response trajectories and predictors for belonging to different trajectory groups.METHODS The Bergen-Stavanger-Innsbruck-Trondheim(BeSt InTro)trial compared the effectiveness of three atypical antipsychotics-amisulpride,aripiprazole,and olanzapine-in a prospective,semirandomized,rater-blind,head-to-head design.Adult participants with a schizophrenia spectrum disorder diagnosis,according to international classification of diseases,Tenth Revision(ICD-10)F20–29,were included.Participants were followed for a period of 12 mo,with assessments at baseline;after one,three and six weeks;and after three,six,nine and 12 mo.A latent class mixed model was fitted to our data.The three-trajectory model based on the Positive and Negative Syndrome Scale(PANSS)total score reduction was found to have adequate fit,and the study drugs,as well as various demographic and clinical parameters,were tested as predictors for belonging to the different trajectory groups.RESULTS Overall,144 participants were included,and 41%completed the 12-mo study period.The largest trajectory group,consisting of 74%of participants,showed a PANSS total score reduction of 59%from baseline to 12 mo(Good response group).A trajectory group comprising 13%of participants had their PANSS total score reduced by 82.5%at 12 mo(Strong response group),while the last response trajectory group comprising 13%of the participants had a PANSS total score reduction of 13.6%(Slight response group).The largest part of the total reduction for the Good and Strong response groups occurred at six weeks of treatment,amounting to 45%and 48%reductions from baseline,respectively.The use of amisulpride predicted belonging to the Strong response group,while unemployment,depression,and negative psychotic symptoms at baseline increased the chance of belonging to the Slight response group,indicating a poor response to antipsychotic drug treatment.CONCLUSION Most of the participants(87%)had a good outcome after one year.Amisulpride users,more often than aripiprazole and olanzapine users,belonged to the response trajectory group with a strong response.

A Qualitative Study on What It Means for Patients with Schizophrenia Living in the Community to Remain on Medication

Background: Little is known about what the experience of “taking antipsychotics” means in a patient’s life. Therefore, this study aims to identify what it means for patients with schizophrenia living in the community to remain on medication. Methods: The participants were five residents of communities, who had been discharged from a psychiatric hospital, but were currently visiting a private psychiatric hospital. In this study, we used participants’ narratives as data and analyzed them according to the procedures described in “An Application of Phenomenological Method in Psychology” (Giorgi, 1975), and “Practice of analyzing materials describing experiences” (Giorgi, 2004). Results: The study results are as follows. 1) The drug may be effective, but Subject (below, S) still wants to take it as little as possible. Meanwhile, S has people who care about S and a person who S can rely on nearby, to manage S’s life. The people above tell S to take medicine, and S takes it. 2) S does not know what kind of medication S is consuming, but recently S has been having a hard time walking;S has people who care for S’s foot and look after S. S thinks taking medicine is for living. 3) S feel some drugs is ineffective. However, S met some people S could trust who passionately recommended the medication to S. S started being careful in remembering to take it. 4) S does not think drugs are necessary for S, but S can interact with people and spend S’s days. S has people who accept S as S is. S continues living in the community while taking medicine that a doctor offers. 5) S was skeptical about the drugs. However, S has a person S can trust, who recommended a way to take the medication in a way that S does not feel overwhelmed. S thinks that it may be a good idea to take it. Conclusions: Based on the analysis of the narratives of each of the five participants, the essential structure was read from the perspective of a third party regarding participants’ medication adherence. A generalized reading of the structure common to the above five essential structures reveals a structure that includes the following three opportunities: 1) Patients realize the importance of people;2) They sometimes entrust themselves to people or follow people’s opinions when taking actions;3) They have come to terms with their initial negative feelings about antipsychotic drugs, subsequently continuing to take antipsychotic drugs. This suggests that the following are important attitudes of supporters of patients with schizophrenia who continue to live in the community: To accept what is happening to the patients, to talk to them with encouragement and compassion, and to be there for them. It is also important for supporters to make patients feel comfortable in opening up while the patients reside in the community and to support patients in making decisions.

Role of presynaptic phosphoprotein synapsin Ⅱ in schizophrenia

Synapsin Ⅱ is a member of the neuronal phosphoprotein family. These phosphoproteins are evolutionarily conserved across many organisms and are important in a variety of synaptic functions, including synaptogenesis and the regulation of neurotransmitter release. A number of genome-wide scans, meta-analyses, and genetic susceptibility studies have implicated the synapsin II gene(3p25) in the etiology of schizophrenia(SZ) and other psychiatric disorders. Further studies have found a reduction of synapsin II m RNA and protein in the prefrontal cortex in post-mortem samples from schizophrenic patients. Disruptions in the expression of this gene may cause synaptic dysfunction, which can result in neurotransmitter imbalances, likely contributing to the pathogenesis of SZ. SZ is a costly, debilitating psychiatric illness affecting approximately 1.1% of the world's population, amounting to 51 million people today. The disorder is characterized by positive(hallucinations, paranoia), negative(social withdrawal, lack of motivation), and cognitive(memory impairments, attention deficits) symptoms. This review provides a comprehensive summary of the structure, function, and involvement of the synapsin family, specifically synapsin II, in the pathophysiology of SZ and possible target for therapeutic intervention/implications.

Effects of antiseizure medications on alternative psychosis and strategies for their application

Forced normalization(FN)is a unique phenomenon that is often seen in the treatment of epilepsy.FN is characterized by abnormal mental behavior and disordered emotions in epilepsy patients despite a significantly improved electroencephalogram and successful seizure control;the occurrence of FN seriously affects patients’quality of life.The causes of FN include antiseizure medications(ASMs),epilepsy surgery and vagus nerve stimulation,with ASMs being the most common cause.However,with the timely reduction or discontinuation of ASMs and the use of antipsychotic drugs,the overall prognosis is good.Here,we perform an extensive review of the literature pertaining to FN,including its epidemiology,possible mechanisms,clinical features,treatment and prognosis.

A temporo-spatial pharmacometabolomics method to characterize pharmacokinetics and pharmacodynamics in the brain microregions by using ambient mass spectrometry imaging

The brain is the most advanced organ with various complex structural and functional microregions. It is often challenging to understand what and where the molecular events would occur for a given drug treatment in the brain. Herein, a temporo-spatial pharmacometabolomics method was proposed based on ambient mass spectrometry imaging and was applied to evaluate the microregional effect of olanzapine(OLZ) on brain tissue and demonstrate its effectiveness in characterizing the microregional pharmacokinetics and pharmacodynamics of OLZ for improved understanding of the molecular mechanism of drugs acting on the microregions of the brain. It accurately and simultaneously illustrated the levels dynamics and microregional distribution of various substances, including exogenous drugs and its metabolites, as well as endogenous functional metabolites from complicated brain tissue. The targeted imaging analysis of the prototype drug and its metabolites presented the absorption, distribution, metabolism, and excretion characteristics of the drug itself. Moreover, the endogenous functional metabolites were identified along with the associated therapeutic and adverse effects of the drug, which can reflect the pharmacodynamics effect on the microregional brain. Therefore, this method is significant in elucidating and understanding the molecular mechanism of central nervous system drugs at the temporo and spatial metabolic level of system biology.