Schizophrenia is composed of a heterogeneous group of patient segments. Our current notion of the heterogeneity in schizophrenia is based on patients presenting with diverse disease symptom ...phenotypes, risk factors, structural and functional neuropathology, and a mixed range of expressed response to treatment. It is important for clinicians to recognize the various clinical presentations of resistance to treatment in schizophrenia and to understand how heterogeneity across treatment resistant patient segments may potentially inform new strategies for the development of effective treatments for Treatment Resistant Schizophrenia (TRS). The heterogeneity of schizophrenia may be reduced by parsing patient segments based on whether patients demonstrate an adequate or inadequate response to treatment. In our current concept of TRS, TRS is defined as non-response to at least two adequate trials of antipsychotic medication and is estimated to affect about 30% of all patients with schizophrenia. In this narrative review, the author discusses that the demonstration of inadequate response to antipsychotic drugs (APDs) may infer that some TRS patients may be suffering from a non-dopamine pathophysiology since D2 receptor antagonist-based treatment is ineffective. Preliminary neurobiological findings may further support the pathophysiologic distinction of TRS from that of general schizophrenia. Investigation of the basis for heterogeneity in TRS through the systematic investigation of relevant "clusters" of similarly at risk individuals may hopefully bring us closer to realize a precision medicine approach for developing effective therapies for TRS patient segments.
Abstract Background Accumulating evidence indicates that glutamatergic tone in schizophrenia may vary as a function of illness duration or medication history. We conducted an exploratory analysis of ...the existing clinical trial database of pomaglumetad methionil (pomaglumetad) to demonstrate treatment response in targeted patient populations. Methods Results of the H8Y-MC-HBBM (HBBM) study and an integrated analysis based on five placebo-controlled trials were summarized. Patients with schizophrenia were randomly assigned to receive either pomaglumetad, 40 or 80 mg twice daily (BID), placebo, or risperidone, 2 mg BID, for up to 6 weeks. Patient subgroups were analyzed to determine the efficacy of pomaglumetad treatment in patients early-in-disease (≤3 years) and late-in-disease (≥10 years) (HBBM, 40 mg, n = 206, 80 mg, n = 198; integrated analysis, 40 mg, n = 382, 80 mg, n = 381) and in patients previously treated with central nervous system drugs with prominent serotonin 2A receptor antagonist activity (S2 group) or with predominant dopamine D2 receptor antagonist activity (D2 group; HBBM, 40 mg, n = 275, 80 mg, n = 269; integrated analysis, 40 mg, n = 590, 80 mg, n = 506). Results In the HBBM study and integrated analysis, only patients early-in-disease or previously treated with D2 drugs exhibited significantly greater improvement relative to those receiving placebo, when treated with pomaglumetad, 40 mg (but not 80 mg) BID. Treatment response to risperidone did not appear to depend upon these patient subgroups. Conclusions Demonstration of antipsychotic efficacy of a potential glutamate-based pharmacotherapy for schizophrenia may require the identification of appropriate patient subgroups whose treatment responsiveness may be fundamentally related to dysregulation of central nervous system glutamatergic tone.
The primary objective of this study was to test the hypothesis that 1 or more dose levels of LY2140023 monohydrate, an oral prodrug of the potent metabotropic glutamate (mGlu) 2/3 receptor agonist ...LY404039, given to patients with schizophrenia for 4 weeks would demonstrate significantly greater efficacy than placebo. The HBBI study was a multicenter, randomized, double-blind, parallel, placebo- and active-controlled trial. Male and female patients aged 18 to 65 years who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia were randomized in a 2:2:2:2:2:1 ratio to receive 5-, 20-, 40-, or 80-mg LY2140023 monohydrate twice daily, placebo twice daily, or placebo (am) and 15 mg of olanzapine (pm) daily. Efficacy was defined as the change from baseline on the Positive and Negative Syndrome Scale (PANSS) total score assessed at 4 weeks. The primary analysis did not show that any of the 4 LY2140023 monohydrate doses were more efficacious than placebo as measured by the PANSS total score. Similarly, olanzapine did not significantly separate from placebo. A higher-than-anticipated treatment effect (14.6-point improvement) in the placebo group was observed on PANSS total score. LY2140023 monohydrate was generally well tolerated, although 4 patients reported the serious adverse event of convulsion. LY2140023 monohydrate-treated patients showed little change in dopamine-related adverse events and weight. The results of the HBBI study are considered to be inconclusive because LY2140023 monohydrate and the active control olanzapine did not separate from placebo in the treatment of patients with acutely exacerbated schizophrenia. Additional efficacy, safety, and tolerability testing are needed.
Animal models are important in preclinical psychopharmacology to study mechanisms and potential treatments for psychiatric disorders. A working group of 14 volunteers, comprising an international ...team of researchers from academia and industry, convened in 2021 to discuss how to improve the translational relevance and interpretation of findings from animal models that are used in preclinical psychopharmacology. The following paper distils the outcomes of the working group’s discussions into 10 key considerations for the planning and reporting of behavioural studies in animal models relevant to psychiatric disorders. These form the iTRIPP guidelines (Improving Translational Relevance In Preclinical Psychopharmacology). These guidelines reflect the key considerations that the group thinks will likely have substantial impact in terms of improving the translational relevance of behavioural studies in animal models that are used to study psychiatric disorders and their treatment. They are relevant to the research community when drafting and reviewing manuscripts, presentations and grant applications. The iTRIPP guidelines are intended to complement general recommendations for planning and reporting animal studies that have been published elsewhere, by enabling researchers to fully consider the most appropriate animal model for the research purpose and to interpret their findings appropriately. This in turn will increase the clinical benefit of such research and is therefore important not only for the scientific community but also for patients and the lay public.
Many individuals who will experience a first episode of psychosis (FEP) are not detected before occurrence, limiting the effect of preventive interventions. The combination of machine-learning ...methods and electronic health records (EHRs) could help address this gap.
This case-control development and validation study is based on EHR data from IBM Explorys. The IBM Explorys Platform holds standardised, longitudinal, de-identified, patient-level EHR data pooled from different health-care systems with distinct EHRs. The present EHR-based studies were retrospective, matched (1:1), case-control studies compliant with RECORD, STROBE, and TRIPOD statements. The study included individuals in the IBM Explorys database who at some point between 1990 and 2018 had a diagnosis of FEP followed by schizophrenia, and psychosis-free matched control individuals from a random subsample of the full cohort. For every individual in the FEP cohort, the individual in the control cohort was matched to have a similar date for inclusion in the database and a similar total observation time. Individuals in the FEP cohort had their index date defined as the first diagnosis of psychosis or the first prescription of antipsychotic medication. Individuals in the control cohort had their index date defined to occur the same number of days after inclusion in the database as their matching FEP individual. The FEP and control cohorts were both randomly split into development and validation datasets in a ratio of 7:3. The subset of individuals in the validation dataset who had all their health-care encounters at providers that were not seen in the development dataset made up the external validation subset. A novel recurrent neural network model was developed to predict the risk of FEP 1 year before the index date by employing demographics and medical events (in the categories diagnoses, prescriptions, procedures, encounters and admissions, observations, and laboratory test results) dynamically collected in the EHR as part of clinical routine. We named the recurrent neural network Dynamic ElecTronic hEalth reCord deTection (DETECT). The main outcomes were accuracy and area under receiver operating characteristic curve (AUROC). Decision-curve analyses and dynamic patient journey plots were used to evaluate clinical usefulness.
The FEP and control cohorts each comprised 72 860 individuals. 102 030 individuals (51 015 matching pairs) were randomly allocated to the development dataset and the remaining 43 690 to the validation dataset. In the validation dataset, 4770 individuals had all their encounters outside of the 118 790 health-care providers that were encountered in the development dataset. The data from these individuals made up the external validation subset. The median follow-up (observation time before index date) was 6·0 years (IQR 3·0–10·4). In the development dataset, DETECT's prognostic accuracy was 0·787 and AUROC was 0·868. In the validation dataset, DETECT's prognostic accuracy was 0·774 and AUROC was 0·856. In the external test subset, DETECT's balanced prognostic accuracy was 0·724 and AUROC was 0·799. Prevalence-adjusted decision-curve analyses suggested that DETECT was associated with a positive net benefit in two different scenarios for FEP detection.
DETECT showed adequate prognostic accuracy to detect individuals at risk of developing a FEP in primary and secondary care. Replication and refinement in a population-based setting are needed to consolidate these findings.
Lundbeck.
Our objective was to prospectively assess whether early (ie, 2 weeks) response to an antipsychotic predicts later (12-week) response and whether 'switching' early non-responders to another ...antipsychotic is a better strategy than 'staying'. This randomized, double-blind, flexible-dosed, 12-week study enrolled 628 patients diagnosed with schizophrenia or schizoaffective disorder. All initiated treatment with risperidone. Early response was defined as > or =20% improvement on the Positive and Negative Syndrome Scale (PANSS) total score following 2 weeks of treatment. Early responders (ERs) continued on risperidone, whereas early non-responders (ENRs) were randomized (1 : 1) to continue on risperidone 2-6 mg/day or switch to olanzapine 10-20 mg/day for 10 additional weeks. Compared with ENRs, risperidone ERs showed significantly greater reduction in PANSS total score (end point; p<001). Early response/non-response was highly predictive of subsequent clinical outcomes. Switching risperidone ENRs to olanzapine at week 2 resulted in a small but significantly greater reduction in PANSS total score (end point; p=0.020) and in depressive symptoms (end point; p=0.004); the reduction in PANSS was greater among those who were still moderately ill at 2 weeks. Switching risperidone ENRs to olanzapine also resulted in significantly greater increases in triglycerides, a significantly greater decrease in prolactin, and significantly less treatment-emergent dyskinesia. This is the first study to prospectively show that early response/non-response to an antipsychotic (risperidone) is a reliable clinical marker of subsequent clinical outcomes and that a 'switching' strategy based on this information may lead to greater clinical improvement than staying on a drug for a longer period in some patients.
To develop a prognostic tool of treatment resistant schizophrenia (TRS) in a large and diverse clinical cohort, with comprehensive coverage of patients using mental health services in four London ...boroughs.
We used the Least Absolute Shrinkage and Selection Operator (LASSO) for time-to-event data, to develop a risk prediction model from the first antipsychotic prescription to the development of TRS, using data from electronic health records.
We reviewed the clinical records of 1,515 patients with a schizophrenia spectrum disorder and observed that 253 (17%) developed TRS. The Cox LASSO survival model produced an internally validated Harrel's C index of 0.60. A Kaplan-Meier curve indicated that the hazard of developing TRS remained constant over the observation period. Predictors of TRS were: having more inpatient days in the three months before and after the first antipsychotic, more community face-to-face clinical contact in the three months before the first antipsychotic, minor cognitive problems, and younger age at the time of the first antipsychotic.
Routinely collected information, readily available at the start of treatment, gives some indication of TRS but is unlikely to be adequate alone. These results provide further evidence that earlier onset is a risk factor for TRS.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The real-world impact of psychosis prevention is reliant on effective strategies for identifying individuals at risk. A transdiagnostic, individualized, clinically-based risk calculator to improve ...this has been developed and externally validated twice in two different UK healthcare trusts with convincing results. The prognostic performance of this risk calculator outside the UK is unknown. All individuals who accessed primary or secondary health care services belonging to the IBM
MarketScan
Commercial Database between January 2015 and December 2017, and received a first ICD-10 index diagnosis of nonorganic/nonpsychotic mental disorder, were included. According to the risk calculator, age, gender, ethnicity, age-by-gender, and ICD-10 cluster diagnosis at index date were used to predict development of any ICD-10 nonorganic psychotic disorder. Because patient-level ethnicity data were not available city-level ethnicity proportions were used as proxy. The study included 2,430,333 patients with a mean follow-up of 15.36 months and cumulative incidence of psychosis at two years of 1.43%. There were profound differences compared to the original development UK database in terms of case-mix, psychosis incidence, distribution of baseline predictors (ICD-10 cluster diagnoses), availability of patient-level ethnicity data, follow-up time and availability of specialized clinical services for at-risk individuals. Despite these important differences, the model retained accuracy significantly above chance (Harrell's C = 0.676, 95% CI: 0.672-0.679). To date, this is the largest international external replication of an individualized prognostic model in the field of psychiatry. This risk calculator is transportable on an international scale to improve the automatic detection of individuals at risk of psychosis.
Abstract This study tested whether treatment with pomaglumetad methionil (LY2140023 monohydrate), a metabotropic glutamate receptor 2/3 agonist compared with placebo (PBO), when added to a fixed-dose ...second-generation antipsychotic (SGA) demonstrated significantly greater reduction of negative symptoms, as assessed by the 16-item Negative Symptom Assessment scale (NSA-16), in patients with schizophrenia. This parallel-group, 16-week study enrolled adults with schizophrenia who were receiving standard of care (SOC) therapy, which included ≥ 3 months treatment with one of four SGAs: aripiprazole, olanzapine, risperidone, or quetiapine. Patients received either 20 mg of twice daily LY2140023 monohydrate (LY2140023) or concurrent PBO SGA. The primary efficacy measure was change from baseline to final visit in NSA-16 total score. Secondary measures included additional measures of efficacy, cognition, and assessments of safety. Of 352 patients screened, 167 were randomly assigned to treatment, and 110 patients completed the study. Patients treated with LY2140023 and SOC failed to demonstrate a statistically significant improvement over patients treated with PBO and SOC on NSA-16 total score at endpoint or at any point during the study (all p > 0.131). Changes in secondary efficacy measures were not significantly different between groups at endpoint. With the exception of vomiting which was greater in the LY2140023 group, there were no statistically significant differences in safety and tolerability measures. This study found no benefit of adjunctive LY2140023 versus PBO for negative symptoms in patients with schizophrenia receiving treatment with SOC. LY2140023 was generally well-tolerated in these patients.
Background:
A proportion of people with treatment-resistant schizophrenia fail to show improvement on clozapine treatment. Knowledge of the sociodemographic and clinical factors predicting clozapine ...response may be useful in developing personalised approaches to treatment.
Methods:
This retrospective cohort study used data from the electronic health records of the South London and Maudsley (SLaM) hospital between 2007 and 2011. Using the Least Absolute Shrinkage and Selection Operator (LASSO) regression statistical learning approach, we examined 35 sociodemographic and clinical factors’ predictive ability of response to clozapine at 3 months of treatment. Response was assessed by the level of change in the severity of the symptoms using the Clinical Global Impression (CGI) scale.
Results:
We identified 242 service-users with a treatment-resistant psychotic disorder who had their first trial of clozapine and continued the treatment for at least 3 months. The LASSO regression identified three predictors of response to clozapine: higher severity of illness at baseline, female gender and having a comorbid mood disorder. These factors are estimated to explain 18% of the variance in clozapine response. The model’s optimism-corrected calibration slope was 1.37, suggesting that the model will underfit when applied to new data.
Conclusions:
These findings suggest that women, people with a comorbid mood disorder and those who are most ill at baseline respond better to clozapine. However, the accuracy of the internally validated and recalibrated model was low. Therefore, future research should indicate whether a prediction model developed by including routinely collected data, in combination with biological information, presents adequate predictive ability to be applied in clinical settings.
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