Response In Schizophrenia Patients Research Articles

Identification of Immune-Related Gene Signature in Schizophrenia.

Schizophrenia (SCZ) is a type of psychiatric disorder characterized by multiple symptoms. Our aim is to decipher the relevant mechanisms of immune-related gene signatures in SCZ. The SCZ dataset and its associated immunoregulatory genes were retrieved using Gene Expression Omnibus (GEO) and single-sample gene set enrichment analysis (ssGSEA). Co-expressed gene modules were determined through weighted gene correlation network analysis (WGCNA). To elucidate the functional characteristics of these clusters, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used. Additionally, gene set enrichment analysis (GSEA) and Gene Set Variation Analysis (GSVA) were conducted to identify enriched pathways for the immune subgroups. A protein-protein interaction (PPI) network analysis was performed to identify core genes relevant to SCZ. A significantly higher immune score was observed in SCZ compared to control samples. Seven distinct gene modules were identified, with genes highlighted in green selected for further analysis. Using the Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) method, degrees of immune cell adhesion and accumulation related to 22 different immune cell types were calculated. Significantly enriched bioprocesses concerning the immunoregulatory genes with differential expressions included interferon-beta, IgG binding, and response to interferon-gamma, according to GO and KEGG analyses. Eleven hub genes related to immune infiltration emerged as key players among the three top-ranked GO terms. This study underscores the involvement of immunoregulatory reactions in SCZ development. Eleven immune-related genes (IFITM1 (interferon induced transmembrane protein 1), GBP1 (guanylate binding protein 1), BST2 (bone marrow stromal cell antigen 2), IFITM3 (interferon induced transmembrane protein 3), GBP2 (guanylate binding protein 2), CD44 (CD44 molecule), FCER1G (Fc epsilon receptor Ig), HLA-DRA (major histocompatibility complex, class II, DR alpha), FCGR2A (Fc gamma receptor IIa), IFI16 (interferon gamma inducible protein 16), and FCGR3B (Fc gamma receptor IIIb)) were identified as hub genes, representing potential biomarkers and therapeutic targets associated with the immune response in SCZ patients.

Niacin skin flush and membrane polyunsaturated fatty acids in schizophrenia from the acute state to partial remission: a dynamic relationship

Despite the consistent finding of an attenuated niacin-induced flush response in schizophrenia, its long-term stability and relationship to the membrane polyunsaturated fatty acid (PUFA) levels remain unknown. We conducted niacin skin tests and measured the membrane PUFAs using gas chromatography among 46 schizophrenia inpatients and 37 healthy controls at the baseline and the 2-month follow-up. Attenuated flush responses were persistently observed in schizophrenia patients in both acute and partial remission states, whereas an increased flush response was found in the controls. A persistent decrease in both dihomo-gamma-linolenic acid and docosahexaenoic acid and an increased turnover of arachidonic acid (ARA) via endogenous biosynthesis were found in schizophrenia patients. A composite niacin flush score by combining those with a control-to-case ratio of >1.4 (i.e., scores at 5 min of 0.1 M, 0.01 M, and 0.001 M + 10 min of 0.01 M and 0.001 M + 15 min of 0.001 M) at the baseline was correlated positively with ARA levels among controls but not among schizophrenia patients, whereas the flush score at the 2-month follow-up was correlated positively with ARA levels among patients. The 2-month persistence of attenuated niacin-induced flush response in schizophrenia patients implies that the niacin skin test might tap a long-term vulnerability to schizophrenia beyond acute exacerbation.

Correlation between telomere length and efficacy of oral and long-acting injectable antipsychotics on severity and cognitive impairment of schizophrenia

Objective To study the correlation between telomere length (TL) and long-acting injectable (LAI) and oral atypical antipsychotic (OAA) efficacy on schizophrenia (SCZ) severity and cognitive impairment. Methods Sixty Schizophrenia patients of 18–50 years and of either sex were included in a 12-week study. Thirty patients were recruited in each group, LAI and OAA. Positive and Negative Syndrome Scale (PANSS) and National Institute of Mental Health and Neuro-Sciences (NIMHANS) neuropsychological battery tests were evaluated at baseline and 12 weeks. TL was estimated at baseline. Results Both groups showed a significant improvement in PANSS and NIMHANS battery test scores after treatment (p < 0.001) within the group, though not between the groups. Mean TL at baseline was 407.58 ± 143.93 and 443.40 ± 178.46 in LAI and OAA groups respectively. A significant negative correlation (r = −0.28, p = 0.03) of TL was seen with the mean change in negative PANSS score after treatment. Conclusions LAI antipsychotics are similar to OAA in decreasing the disorder severity and improving the cognitive impairment in schizophrenia. Also, patients who have shorter TL show greater improvement in the negative PANSS score. Hence, TL holds the potential of predicting antipsychotic drug response in schizophrenia patients. KEY POINTS Long-acting injectable antipsychotic was comparable to oral atypical antipsychotics in bringing out improvement in disorder severity, cognitive functions over 12 weeks. Shorter telomere length has been found to be associated with a greater response in negative symptoms of schizophrenia.

Gut microbial biomarkers for the treatment response in first-episode, drug-na\xefve schizophrenia: a 24-week follow-up study

Preclinical studies have shown that the gut microbiota can play a role in schizophrenia (SCH) pathogenesis via the gut-brain axis. However, its role in the antipsychotic treatment response is unclear. Here, we present a 24-week follow-up study to identify gut microbial biomarkers for SCH diagnosis and treatment response, using a sample of 107 first-episode, drug-naïve SCH patients, and 107 healthy controls (HCs). We collected biological samples at baseline (all participants) and follow-up time points after risperidone treatment (SCH patients). Treatment response was assessed using the Positive and Negative Symptoms Scale total (PANSS-T) score. False discovery rate was used to correct for multiple testing. We found that SCH patients showed lower α-diversity (the Shannon and Simpson’s indices) compared to HCs at baseline (p = 1.21 × 10−9, 1.23 × 10−8, respectively). We also found a significant difference in β-diversity between SCH patients and HCs (p = 0.001). At baseline, using microbes that showed different abundance between patients and controls as predictors, a prediction model can distinguish patients from HCs with an area under the curve (AUC) of 0.867. In SCH patients, after 24 weeks of risperidone treatment, we observed an increase of α-diversity toward the basal level of HCs. At the genus level, we observed decreased abundance of Lachnoclostridium (p = 0.019) and increased abundance Romboutsia (p = 0.067). Moreover, the treatment response in SCH patients was significantly associated with the basal levels of Lachnoclostridium and Romboutsia (p = 0.005 and 0.006, respectively). Our results suggest that SCH patients may present characteristic microbiota, and certain microbiota biomarkers may predict treatment response in this patient population.

Source decomposition of the frontocentral auditory steady-state gamma band response in schizophrenia patients and healthy subjects.

Gamma-band auditory steady-state response (ASSR) is a neurophysiologic index that is increasingly used as a translational biomarker in the development of treatments of neuropsychiatric disorders. While gamma-band ASSR is generated by distributed networks of highly interactive temporal and frontal cortical sources, the majority of human gamma-band ASSR studies using electroencephalography (EEG) highlight activity from only a single frontocentral scalp site, Fz, where responses tend to be largest and reductions in schizophrenia patients are most evident. However, no previous study has characterized the relative source contributions to Fz, which is a necessary step to improve the concordance of preclinical and clinical EEG studies. A novel method to back-project the contributions of independent cortical source components was applied to assess the independent sources and their proportional contributions to Fz as well as source-resolved responses in 432 schizophrenia patients and 294 healthy subjects. Independent contributions of gamma-band ASSR to Fz were detected from orbitofrontal, bilateral superior/middle/inferior temporal, bilateral middle frontal, and posterior cingulate gyri in both groups. In contrast to expectations, the groups showed comparable source contribution weight to gamma-band ASSR at Fz. While gamma-band ASSR reductions at Fz were present in schizophrenia patients consistent with previous studies, no group differences in individual source-level responses to Fz were detected. Small differences in multiple independent sources summate to produce scalp-level differences at Fz. The identification of independent source contributions to a single scalp sensor represents a promising methodology for measuring dissociable and homologous biomarker targets in future translational studies.

MicroRNA-195 predicts olanzapine response in drug-free patients with schizophrenia: A prospective cohort study.

Disturbances of microRNA-195 have been implicated in the pathogenesis of schizophrenia. However, microRNA-195 levels in schizophrenia are controversial. To the best of our knowledge, this is the first study to examine microRNA-195 levels in untreated schizophrenia patients and their relationship to olanzapine response. We recruited 81 untreated schizophrenia patients and 96 healthy controls. The patients received 2 months olanzapine treatment. MicroRNA-195 levels in peripheral blood mononuclear cells were measured using quantitative real-time polymerase chain reaction testing. Psychiatric symptoms were assessed using the Positive and Negative Syndrome Scale. No significant differences in microRNA-195 levels were found between patients and healthy controls (p > 0.05). Olanzapine significantly reduced microRNA-195 levels after 2 months treatment (p = 0.003). Interestingly, microRNA-195 levels decreased significantly in responders (p = 0.010), but not in non-responders (p > 0.05). Both baseline microRNA-195 levels (p = 0.027, p = 0.030) and the reduction rate of microRNA-195 levels (p = 0.034, p = 0.044) were positively associated with the reduction rate of Positive and Negative Syndrome Scale total score and general psychopathological subscale score. Multiple stepwise regression analysis revealed that baseline microRNA-195 level was an independent contributor to the reduction in Positive and Negative Syndrome Scale total score and the general psychopathological subscale score (p = 0.018, p = 0.030). Finally, logistic regression analysis suggested that baseline microRNA-195 level can serve as a biomarker for response to olanzapine (p = 0.037). Our data indicate that microRNA-195 level may predict symptomatic improvement and olanzapine response in schizophrenia patients, suggesting that microRNA-195 should be considered as a potential therapeutic target for antipsychotics.

Prediction of individual responses to electroconvulsive therapy in patients with schizophrenia: Machine learning analysis of resting-state electroencephalography

BackgroundElectroconvulsive therapy (ECT) has strong efficacy in patients with treatment refractory schizophrenia. However, access to ECT has been limited by high costs, professional labor, treatment duration, and significant adverse effects. To provide support for the decision to perform ECT, we aimed to predict individual responses to ECT among patients with schizophrenia using machine learning analysis of resting-state electroencephalography (EEG). MethodsForty-seven patients diagnosed with schizophrenia or schizoaffective disorder with EEG recordings before the course of ECT were treated at Seoul National University Hospital. Among these patients, 29 were responders who showed scores of 3 or less on the Clinical Global Impression Severity scale after the course of ECT. Transfer entropy (TE), which represents information flow, was extracted from baseline EEG data and used as a feature. Feature selection was performed with four methods, including Random Subset Feature Selection (RSFS). The random forest classifier was used to predict individual ECT responses. ResultsThe averaged TE, especially in frontal regions, was higher in ECT responders than in nonresponders. A predictive model using the RSFS method classified ECT responders and nonresponders with 85.3% balanced accuracy, 85.2% accuracy, 88.7% sensitivity, and 81.8% specificity. The positive predictive value was 82.6%, and the negative predictive value was 88.2%. ConclusionsThe results of the current study suggest that higher effective connectivity in frontal areas may be associated with a favorable ECT response. Furthermore, personalized decisions to perform ECT in clinical practice could be augmented by resting-state EEG biomarkers of the ECT response in schizophrenia patients.

A proteomic signature associated to atypical antipsychotic response in schizophrenia patients: a pilot study.

A major hurdle faced by most schizophrenia patients is the poor efficacy of current antipsychotic medications. This stems from a poor understanding of the underlying pathophysiology and the lack of biomarkers for the prediction of a positive medication response. By employing state-of-the-art proteomic analysis of blood plasma from 58 patients who were either drug-naive or drug-free at the time of sample collection, we identified potential biomarkers that were predictive of a positive response after 6weeks of treatment with antipsychotics. Complement and coagulation cascades were the most over-represented biological pathways among these proteins, consistent with the importance of these processes in schizophrenia. Although preliminary, these findings are novel and may drive future efforts in the development of predictive tests for medication efficacy and thereby have a positive influence on disease outcome.

Profiling inflammatory signatures of schizophrenia: A cross-sectional and meta-analysis study

We aimed to profile a broad panel of inflammatory markers in patients with schizophrenia and healthy controls. Additionally, we performed a meta-analysis of chemokine alterations that have not been subjected to quantitative synthesis so far. We recruited 78 patients with schizophrenia and 78 healthy controls, and measured inflammatory markers using the Luminex technology. After adjustment for multiple testing, we found elevated levels of interleukin (IL)-1 receptor antagonist (IL-1RA), IL-6, IL-7, IL-8, IL-9, IL-10, IL-13, interferon-γ, eotaxin-1, granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1), platelet-derived growth factor with two B subunits (PDGF-BB), macrophage inflammatory protein (MIP)-1α, MIP-1β, vascular endothelial growth factor A (VEGF-A) and RANTES in multiple-episode schizophrenia (MES) patients. These differences, except for the difference in eotaxin-1 levels, appeared to be significant after co-varying for the dosage of antipsychotics. There were no significant differences in the levels of immune markers between first-episode schizophrenia (FES) patients and controls. Our meta-analysis revealed elevated levels of MCP-1 in first-episode psychosis (FEP) patients and MES individuals. Other chemokine alterations (elevated levels of IL-8, eotaxin-1 and MIP-1β) were present only in MES patients. Our results indicate that dysregulation of immune response in schizophrenia develops with illness progression or appears as a long-term medication effect. Chemokine alterations are another example of aberrant immune response in schizophrenia patients. Elevated levels of MCP-1 might represent trait markers since these alterations were found in FEP and MES patients. Other chemokine alterations might be the markers of disease progression or might represent medication effects.

M54 - Pharmaco-Epigenomic Response of Antipsychotic Drugs In Theranostics of Schizophrenia

Background Antipsychotic drugs are considered as the first line treatment for psychotic disorders including Schizophrenia. The patients receiving antipsychotic medications show a wide variability in drug response and drug induced side effects which could be attributed to genetic or non-genetic components influencing drug response. Epigenetic mechanisms can offer an alternate mechanism for interindividual drug variability which cannot be explained by genetic polymorphisms. The present study involves evaluating the epigenetic modifications induced by antipsychotic drugs, first in an in-vitro system and then follows it up, to understand its implication in therapeutic response in schizophrenia patients. Methods In the in-vitro study, HepG2, a liver cell line was treated with various antipsychotic drugs including haloperidol, clozapine and olanzapine in varying concentrations for different time interval, either individually or in combination. Various epigenetic parameters were measured at global as well as gene specific level post antipsychotic treatment. Assessment of global DNA methylation and global histone modifications were carried out. The gene expression status of various epigenetic genes and pharmacologically relevant genes and their target miRNA profiles were also evaluated. The conclusions from in-vitro data were extrapolated to a clinical setting by validating the observations between schizophrenia and healthy subjects and between drug responsive and non-responsive schizophrenia patients. Results Our in-vitro data showed that antipsychotic drugs induced increase in global DNA methylation at 5-methylcytosine and 5-hydroxymethylcytosine level in a dosage and time dependent manner. These alterations in methylation were attributed to the increase in gene expression of various epigenetic genes including DNA methyltransferases, methyl CpG binding proteins and DNA demethylases which in turn was regulated by their target microRNAs. The gene expression of various pharmacologically relevant genes including multi drug transporter and drug metabolizing enzymes were upregulated by antipsychotic drugs and this was mediated by altered expression of miRNAs that regulate these genes. Validation of in-vitro observations in a clinical setting have shown that global DNA methylation, epigenetic as well as pharmacologically relevant gene expression and their target microRNA expression was significantly different between drug responders, non responders and controls. Also the epigenetic alterations were markedly associated with drug response rather than disease pathogenesis. Discussion Our in-vitro data followed up with clinical data suggest that antipsychotic drugs can modulate the epigenome. The responsiveness to antipsychotic drugs shown by Schizophrenia patients is due to various epigenetic events induced by antipsychotic drugs, clearly suggesting the epigenetic mode of action of antipsychotic drugs. The study also highlights that the reported epigenetic alteration in schizophrenia may be influenced by antipsychotic drugs and not precisely for pathogenesis. The outcome of the study would help us to understand the role of epigenetic mechanisms in the pharmacological effects of antipsychotic medications and address the issue of interindividual variability in drug response.

Response preparation and intra-individual reaction time variability in schizophrenia.

Background. It is important to prepare response in advance to increase the efficiency of its execution. The process of response preparation is usually studied using the precueing paradigm. In this paradigm subjects have to employ the preceding information about further imperative stimulus to perform proper response preparation, which shortens the reaction time of subsequent response execution. Previous studies detected the impairment of response preparation in schizophrenia only with the help of electroencephalographic parameters, but not with the assessing of reaction time. Therefore, in this study we attempted to find a behavioural parameter that could detect impairment in response preparation of schizophrenia patients. It was recently found that appropriate response preparation not only shortens the reaction time but also increases its stability, which is measured with the intra-individual reaction time variability. It was also revealed that response stability could better find cognitive dysfunction in some studies of schizophrenia disorder than classical behavioural parameters. Hence, the main goal of this study was to verify if intra-individual reaction time variability could detect the impairment of response preparation in schizophrenia patients.Materials and methods. In order to achieve the main purpose, we carried out a study with 14 schizophrenia patients and 14 control group subjects. We used precueing paradigm in our research, in which participants had to employ information about stimulus probability for the proper response preparation.Results. Our main result showed that despite the responses of schizophrenia patients were faster to the high-probability stimulus than to the low-probability one (F (1, 13) = 30.9, p < 0.001), intra-individual reaction time variability did not differ in this group between the responses to more and less probable stimuli (F (1, 13) = 0.64, p = 0.44).Conclusions. Results of the study suggest that people with schizophrenia were able to use precueing probabilistic information only to shorten their reaction time, but not to increase response stability. Therefore, it was found that intra-individual reaction time variability parameter could detect response preparation impairment in schizophrenia, and could be used in clinical purposes.

Neuronal effects of nicotine during auditory selective attention in schizophrenia.

Although nicotine has been shown to improve attention deficits in schizophrenia, the neurobiological mechanisms underlying this effect are poorly understood. We hypothesized that nicotine would modulate attention-associated neuronal response in schizophrenia patients in the ventral parietal cortex (VPC), hippocampus, and anterior cingulate based on previous findings in control subjects. To test this hypothesis, the present study examined response in these regions in a cohort of nonsmoking patients and healthy control subjects using an auditory selective attention task with environmental noise distractors during placebo and nicotine administration. In agreement with our hypothesis, significant diagnosis (Control vs. Patient) X drug (Placebo vs. Nicotine) interactions were observed in the VPC and hippocampus. The interaction was driven by task-associated hyperactivity in patients (relative to healthy controls) during placebo administration, and decreased hyperactivity in patients after nicotine administration (relative to placebo). No significant interaction was observed in the anterior cingulate. Task-associated hyperactivity of the VPC predicted poor task performance in patients during placebo. Poor task performance also predicted symptoms in patients as measured by the Brief Psychiatric Rating Scale. These results are the first to suggest that nicotine may modulate brain activity in a selective attention-dependent manner in schizophrenia.

Polymorphisms in PLA2G6 and PLA2G4C genes for calcium-independent phospholipase A2 do not contribute to attenuated niacin skin flush response in schizophrenia patients

We hypothesized that attenuated niacin skin flushing in schizophrenia patients might be associated with polymorphic variants in PLA2G6 and PLA2G4C genes (rs4375 and rs1549637 variations) which encode calcium-independent phospholipase A2 beta (iPLA2β) and cytosolic phospholipase A2 gamma (cPLA2γ) enzymes. The iPLA2β and cPLA2γ may play an important role in niacin-mediated signaling; in addition to their major role – mediating phospholipids remodeling, which alters membrane receptors and signal transduction, they regulate the reservoir of arachidonic acid for prostaglandins synthesis. Skin response to topical niacin of 0.1M, 0.01M, 0.001M and 0.0001M concentrations in 75 schizophrenia patients was rated using the method of volumetric niacin response (VNR). Neither PLA2G6 nor PLA2G4C gene polymorphisms were significantly associated with VNR values. Furthermore, polymorphisms׳ synergy on niacin skin flushing was also not detected.

Synergistic association of PI4KA and GRM3 genetic polymorphisms with poor antipsychotic response in south Indian schizophrenia patients with low severity of illness.

Literature indicates key role of glutamatergic pathway genes in antipsychotic response among schizophrenia patients. However, molecular basis of their underlying role in antipsychotic response remained unexplained. Thus, to unravel their molecular underpinnings, we sought to investigate interactions amongst GRM3, SLC1A1, SLC1A2, SLC1A3, SLC1A4 gene polymorphisms with drug response in south Indian schizophrenia patients. We genotyped 48 SNPs from these genes in 423 schizophrenia patients stratified into low and high severity of illness groups. The SNPs and haplotypic combinations of associated SNPs were examined for their association with antipsychotic response. Multifactor-dimensionality-reduction was further used to explore gene-gene interaction among these SNPs and 53 SNPs from previously studied genes (BDNF, RGS4, SLC6A3, PI4KA, and PIP4K2A). Single SNP and haplotype analyses revealed no significant association with drug response irrespective of severity of illness. Gene-gene interaction analyses yielded promising leads, including an observed synergistic effect between PI4KA_rs165854 and GRM3_rs1468412 polymorphisms and incomplete antipsychotic response in schizophrenia patients with low severity of illness (OR = 12.4; 95%CI = 3.69-41.69). Further, this interaction was also observed in atypical monotherapy (n = 355) and risperidone (n = 260) treatment subgroups (OR = 11.21; 95%CI = 3.30-38.12 and OR = 13.5; 95%CI = 3.03-121.61 respectively). PI4KA is known to be involved in the biosynthesis of phosphatidylinositol-4, 5-bisphosphate which regulates exocytotic fusion of synaptic vesicles (glutamate, dopamine) with the plasma membrane and regulates duration of signal transduction of GPCRs. Whereas GRM3 regulates glutamate and dopamine transmission. Present findings indicate that PI4KA and GRM3 polymorphisms have potential to jointly modulate antipsychotic response. These results warrant additional replication studies to shed further light on these interactions.

Genetic variations of PIP4K2A confer vulnerability to poor antipsychotic response in severely ill schizophrenia patients.

Literature suggests that disease severity and neurotransmitter signaling pathway genes can accurately identify antipsychotic response in schizophrenia patients. However, putative role of signaling molecules has not been tested in schizophrenia patients based on severity of illness, despite its biological plausibility. In the present study we investigated the possible association of polymorphisms from five candidate genes RGS4, SLC6A3, PIP4K2A, BDNF, PI4KA with response to antipsychotic in variably ill schizophrenia patients. Thus in present study, a total 53 SNPs on the basis of previous reports and functional grounds were examined for their association with antipsychotic response in 423 schizophrenia patients segregated into low and high severity groups. Additionally, haplotype, diplotype, multivariate logistic regression and multifactor-dimensionality reduction (MDR) analyses were performed. Furthermore, observed associations were investigated in atypical monotherapy (n = 355) and risperidone (n = 260) treated subgroups. All associations were estimated as odds ratio (OR) and 95% confidence interval (CI) and test for multiple corrections was applied. Single locus analysis showed significant association of nine variants from SLC6A3, PIP4K2A and BDNF genes with incomplete antipsychotic response in schizophrenia patients with high severity. We identified significant association of six marker diplotype ATTGCT/ATTGCT (rs746203-rs10828317-rs7094131-rs2296624-rs11013052-rs1409396) of PIP4K2A gene in incomplete responders (corrected p-value = 0.001; adjusted-OR = 3.19, 95%-CI = 1.46–6.98) with high severity. These associations were further observed in atypical monotherapy and risperidone sub-groups. MDR approach identified gene-gene interaction among BDNF_rs7103411-BDNF_rs1491851-SLC6A3_rs40184 in severely ill incomplete responders (OR = 7.91, 95%-CI = 4.08–15.36). While RGS4_rs2842026-SLC6A3_rs2975226 interacted synergistically in incomplete responders with low severity (OR = 4.09, 95%-CI = 2.09–8.02). Our findings provide strong evidence that diplotype ATTGCT/ATTGCT of PIP4K2A gene conferred approximately three-times higher incomplete responsiveness towards antipsychotics in severely ill patients. These results are consistent with the known role of phosphatidyl-inositol-signaling elements in antipsychotic action and outcome. Findings have implication for future molecular genetic studies as well as personalized medicine. However more work is warranted to elucidate underlying causal biological pathway.

EPA-0446 – Trajectories of antipsychotic response in drug-naive schizophrenia patients: results from the 6-month espass follow-up study

Objective The aim of the present study was to explore any heterogeneity in the 6-month clinical response in antipsychotic drug-naive schizophrenia patients, and to determine predictors of that outcome. Method 467 antipsychotic drug-naive schizophrenia patients were included in France nationwide and followed up over 6 months. In order to identify trajectories of clinical response, a latent class growth analysis was performed using the Clinical Global Impression-Severity (CGI-S) scores at baseline, 1, 3 and 6 months. Regression models were used to identify predictors of trajectory membership. Results Five trajectory groups were identified: a rapid response group (n=45), a gradual response group (n=204), patients remaining mildly ill (n=133), patients remaining very ill (n=23) and a group with unsustained clinical response (n=62). Predictors of the 6-month clinical response were baseline CGI-S score (odds ratio 3.1; 95% confidence interval, 2.1-4.4) and negative symptoms (OR 1.5; 95%CI, 1.2-1.9). The sole predictor of rapid response as compared to gradual response was employment (OR 2.5; 95%CI, 1.2-4.9). Conclusion Clinical response in schizophrenia patients 6 months after a first-ever antipsychotic drug initiation is heterogeneous. Therapeutic strategies in first episode should take account of symptoms severity and of early clinical response, in order to maximize the chances of recovery.

Influencing Factors and Predictors of Early Response in Schizophrenia Patients Receiving the Paliperidone Extended-Release Tablets (Paliperidone ER)

ObjectivePaliperidone extended-release tablet (paliperidone ER) is a new oral psychotropic agent developed for schizophrenia treatment. There have been some studies about paliperidone's good efficacy and tolerability. Clinicians appear to change the antipsychotic medication to paliperidone ER. However, it is not known what patients are favorable responsive to paliperidone ER. The aim of this study was to evaluate the characteristics of early responders and investigate predictors of acute response when the medications changed to paliperidone ER.MethodsData were analyzed from schizophrenic patients who participated in a multi-center, open-label, non-comparative clinical trial. Total 320 patients were examined in this study. Sociodemographic, psychopathology, social function and metabolic data were evaluated. Unpaired t-test for continuous and χ2 for categorical data, respectively, were used to compare early responder and non-responders. Logistic regression analysis was used to establish a prediction model.Results38.7% of study subjects (124 of 320) responded to paliperidone ER treatment. Logistic regression analysis showed that a good paliperidone ER response was more likely when patients were social drinkers, when patients had started medication at inpatient, when negative symptoms were less severe, and when patients' social relationship and self-care were better.ConclusionEarly response to paliperidone ER treatment is associated with less negative symptoms and good social relationships and self-care. Strategies to reduce these symptoms may contribute to early response to paliperidone ER.

The impact of PLA2G4A and PTGS2 gene polymorphisms, and red blood cell PUFAs deficit on niacin skin flush response in schizophrenia patients

We investigated the etiology of the attenuated niacin skin flush response in schizophrenia patients. Skin response to topical niacin of 0.1M, 0.01M, 0.001M, and 0.0001M concentrations was rated using method of volumetric niacin response (VNR) and correlated to two functional A/G polymorphisms in genes: phospholipase A2 group IVA (BanI of the PLA2G4A), and rs689466 of the prostaglandin synthase-2 (PTGS2). We further tested the possible correlation between niacin response and fatty acid (FA) content of red blood cells (RBCs). We detected statistically significant but weak impact of both polymorphisms on niacin flush response in schizophrenia patients. The dosage of the G alleles of both polymorphisms was associated with higher VNR values, although each polymorphic variant accounted for only 1% of the overall flush response variability. Regarding FA content, both n−3 and n−6 polyunsaturated FAs (PUFAs) were significantly reduced in the patient group, but an association with niacin sensitivity was not detected.

The functional coding variant Asn107Ile of the neuropeptide S receptor gene (NPSR1) is associated with schizophrenia and modulates verbal memory and the acoustic startle response

Recently, the neuropeptide S (NPS) neurotransmitter system has been identified as a promising psychopharmacological drug target given that NPS has shown anxiolytic-like and stress-reducing properties and memory-enhancing effects in rodent models. NPS binds to the G-protein-coupled receptor encoded by the neuropeptide S receptor gene (NPSR1). A functional variant within this gene leads to an amino-acid exchange (rs324981, Asn107Ile) resulting in a gain-of-function in the Ile107 variant which was recently associated with panic disorder in two independent studies. A potential psychopharmacological effect of NPS on schizophrenia psychopathology was demonstrated by showing that NPS can block NMDA antagonist-induced deficits in prepulse inhibition. We therefore explored a potential role of the NPSR1 Asn107Ile variation in schizophrenia. A case-control sample of 778 schizophrenia patients and 713 healthy control subjects was successfully genotyped for NPSR1 Asn107Ile. Verbal declarative memory and acoustic startle response were measured in subsamples of the schizophrenia patients. The case-control comparison revealed that the low-functioning NPSR1 Asn107 variant was significantly associated with schizophrenia (OR 1.19, p=0.017). Moreover, specifically decreased verbal memory consolidation was found in homozygous Asn107 carriers while memory acquisition was unaffected by NPSR1 genotype. The schizophrenia patients carrying the Ile107 variant demonstrated significantly reduced startle amplitudes but unaffected prepulse inhibition and habituation. The present study confirms findings from rodent models demonstrating an effect of NPS on memory consolidation and startle response in schizophrenia patients. Based on these findings, we consider NPS as a promising target for antipsychotic drug development.

Lessons from MATRICS

Lessons from MATRICS