Optimal thresholds of early response to atypical antipsychotics: Application of signal detection methods

Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, DC 4133, Indianapolis, IN 46285, USA.
Schizophrenia Research (Impact Factor: 4.43). 07/2009; 113(1):34-40. DOI: 10.1016/j.schres.2009.06.001
Source: PubMed

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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 12/2014; 165(8). DOI:10.1002/ajmg.b.32268 · 3.27 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate the clinical value of early partial symptomatic improvement in predicting the probability of response during the short-term treatment of bipolar depression. Blinded data from 10 multicenter, randomized, double-blind, placebo-controlled trials in bipolar I or II depression were used to determine if early improvement (≥20% reduction in depression symptom severity after 14 days of treatment) predicted later short-term response or remission. Sensitivity, specificity, efficiency, and positive and negative predictive values (PPV, NPV) were calculated using an intent to treat analysis of individual and pooled study data. 1913 patients were randomized to active compounds (aripiprazole, lamotrigine, olanzapine/olanzapine-fluoxetine, and quetiapine), and 1456 to placebo. In the pooled positive studies, early improvement predicted response and remission with high sensitivity (86% and 88%, respectively), but rates of false positives were high (53% and 59%, respectively). Pooled negative predictive values for response/remission (i.e. confidence in knowing the drug will not result in response or remission) were 74% and 82%, respectively, with low rates of false negatives (14% and 12%, respectively). Early improvement in an individual patient does not appear to be a reliable predictor of eventual response or remission due to an unacceptably high false positive rate. However, the absence of early improvement appears to be a highly reliable predictor of eventual non-response, suggesting that clinicians can have confidence in knowing when a drug is not going to work during short-term treatment. Patients who fail to demonstrate early improvement within the first two weeks of treatment may benefit from a change in therapy.
    Journal of Affective Disorders 11/2010; 130(1-2):171-9. DOI:10.1016/j.jad.2010.10.026 · 3.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Functional improvement is generally thought to be distal to improvement in psychiatric symptoms in patients with schizophrenia. In this study, we assessed the effects of early response/non-response to an atypical antipsychotic across multiple outcome measures. This was a randomized, double-blind, flexible-dose, 12-week study that enrolled chronically-ill patients (n=628) diagnosed with schizophrenia or schizoaffective disorder who were experiencing acute symptom exacerbation. Patients were initially assigned to risperidone drug therapy (2-6 mg/day), and their response status at 2 weeks was determined. Early responders (ERs) continued with risperidone therapy, whereas early non-responders (ENRs) were randomized (1:1) in a double-blind manner to either continue on risperidone or switch to another atypical antipsychotic for 10 additional weeks of therapy. Subsequent treatment outcomes were measured by the Quality of Life Scale (QLS), Schizophrenia Objective Functioning Instrument (SOFI), and Subjective Well-being under Neuroleptics (SWN-K) scale. Compared to ENRs, ERs to risperidone showed significantly more improvement from baseline to endpoint on the QLS total score and all 4 categories (p<.01), the SOFI overall global score and all 4 domains (p<.001), and the SWN-K total score and all 5 subscales (p<.05). Among ERs, the majority of improvement had already been attained by Week 2. There was concordance among clinician- and patient-rated scales across outcomes. Improvement across multiple outcome dimensions was not delayed relative to improvement in psychiatric symptoms. Rather, patients who showed an early response to antipsychotic treatment as defined by improvement in psychiatric symptoms also showed early and consistent improvement in functioning, quality of life, and subjective well-being.
    Schizophrenia Research 05/2010; 118(1-3):176-82. DOI:10.1016/j.schres.2009.12.013 · 4.43 Impact Factor