Optimal thresholds of early response to atypical antipsychotics: application of signal detection methods.
ABSTRACT Identify the optimal magnitude of response to antipsychotic medication at various early time points that best predicts subsequent non-response at 8 weeks.
Data were pooled from 5 randomized, double-blind clinical trials of atypical antipsychotics in the treatment of schizophrenia and related disorders (n=1137 moderately-to-severely ill; n=300 less than moderately ill). Signal detection methods (receiver-operating characteristic curves) were used to identify the optimal response threshold based on percent change from baseline on the PANSS total score at different early time points (Weeks 1-4) to predict subsequent 'non-response' at 8 weeks (i.e., not 'minimally improved', 'much improved' or 'remitted') while holding the false positive rate to a level of 30% or less. Analyses were implemented separately for patients with schizophrenia who differed on baseline illness severity.
Using Area Under the Curve (AUC) >or=0.8 to define optimal discriminative ability at the earliest time point, the early response threshold in moderately-to-severely ill patients for predicting not 'minimally improved' was <15% reduction in PANSS total at Week 2, not 'much improved' was <23% at Week 2, and not 'remitted' was <26% at Week 4. Similarly, in less than moderately ill patients, the optimal early response threshold for predicting not 'minimally improved' was <12% reduction in PANSS total at Week 2, and not 'much improved' was <14% at Week 1.
Specific thresholds of response were identified at early time points for predicting subsequent non-response. Not attaining these early response thresholds may serve as important clinical markers of subsequent non-response to antipsychotic therapy.
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ABSTRACT: 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.PLoS ONE 07/2014; 9(7):e102556. · 3.53 Impact Factor
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ABSTRACT: Remission seems achievable for a portion of schizophrenic patients. This study aimed to identify the early predictors for remission and to establish an optimal prediction model. One hundred thirty-five acutely ill schizophrenic inpatients received 150-mg/d zotepine treatment for 4 weeks. Psychopathologic severity was assessed weekly using the Brief Psychiatric Rating Scale (BPRS). Symptomatic remission was defined according to the consensus criteria proposed by Andreasen et al. Backward stepwise logistic regression model was used to obtain the early predictors. The receiver operating characteristic curve was used to determine the cutoff point of predictors. The study was conducted from June 2004 to April 2005. Twenty-one (21.0%) of 100 completers remitted after 4 weeks of treatment. The most influential predictors for ultimate remission were percentage of BPRS score reduction at week 2 and BPRS remission-items score at week 2. Brief Psychiatric Rating Scale score reduction at week 2 of 35% and BPRS remission-items score of 18 at week 2 seemed to be the optimal cutoff points. They provided a sensitivity of 62% and 84% and a specificity of 86% and 65%. Patients with less than a 35% BPRS score reduction and a BPRS remission-items score larger than 18 during the first 2 weeks of treatment were unlikely to reach a final remission. Whether the finding can be extrapolated to other validated assessment scales and other antipsychotics require further studies.Journal of clinical psychopharmacology 11/2012; · 5.09 Impact Factor
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ABSTRACT: The Paliperidone ER Treatment in Acute Intervention (PERTAIN) study was designed to explore treatment response, tolerability, and safety of flexible doses of paliperidone ER in patients with schizophrenia admitted for an acute exacerbation. This paper addresses a secondary analysis of PERTAIN data designed to explore predictors for treatment response, flexible dosing, and concomitant benzodiazepine use. This prospective, multicenter, phase 3b, open-label, single-arm, 6-week study used flexible doses of paliperidone ER (3 to 12mg once daily) to treat patients hospitalized for an acute exacerbation of schizophrenia, reflecting more closely daily clinical practice. Predictive models were evaluated for paliperidone ER flexible dosing, treatment response, and concomitant treatment with benzodiazepines as distinct independent variables. For the analysis of explanatory variables, a stepwise logistic regression was used, taking into account patient age, gender, body mass index, diagnosis and duration of schizophrenia, number of prior hospitalizations, psychotic symptoms (PANSS), disease severity (CGI-S), and patient functioning (PSP) at baseline. Early response (defined as response within 2weeks of treatment initiation) was also used as a predictor. Clinical response (defined as ≥30% decrease in PANSS total score and ≥1 point decrease in CGI-S from baseline to endpoint) was predicted by early clinical response (p<0.001) and there was a trend for the diagnosis of paranoid schizophrenia vs. other types of schizophrenia to predict clinical response (p=0.0525). High response (defined as ≥50% decrease in PANSS total score and ≥2 points decrease in CGI-S from baseline to endpoint) was predicted by early high response, higher baseline CGI-S, or female gender. More severely ill patients with a higher baseline CGI-S were twice likely to be treated concomitantly with a benzodiazepine.Progress in Neuro-Psychopharmacology and Biological Psychiatry 10/2013; · 4.03 Impact Factor