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: 3.92). 07/2009; 113(1):34-40. DOI: 10.1016/j.schres.2009.06.001
Source: PubMed


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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    • "Hence, early response toward medication is a predictor of long-term response (Kinon et al. 2010). Therefore, it is important to investigate the role of clinical and genetic factors in the therapeutic outcome in patients with differential range of disease severity (Chen et al. 2009). A number of genome-wide association studies (GWASs), postmortems, and animal studies (Ikeda et al. 2010; McClay et al. 2011) have implicated the role of susceptibility genes and related neurodevelopment pathways in schizophrenia pathophysiology and treatment outcome (Banerjee et al. 2010; Iasevoli et al. 2014). "
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    ABSTRACT: Neurodevelopmental and neuroimmunological genes critically regulate antipsychotic treatment outcome. We report genetic associations of antipsychotic response in 742 schizophrenia patients from Indian populations of Indo-European and Dravidian ancestry, segregated by disease severity. Meta-analysis comparing the two populations identified CCL2 [rs4795893: OR (95% CI) = 1.79 (1.27–2.52), P = 7.62 × 10−4; rs4586: OR (95% CI) = 1.74 (1.24–2.43), P = 1.13 × 10−3] and GRIA4 [rs2513265: OR (95% CI) = 0.53 (0.36–0.78), P = 1.44 × 10−3] in low severity group; and, ADCY2 [rs1544938: OR (95% CI) = 0.36 (0.19–0.65), P = 7.68 × 10−4] and NRG1 [rs13250975, OR (95% CI) = 0.42 (0.23–0.79), P = 6.81 × 10−3; rs17716295, OR (95% CI) = 1.78 (1.15–2.75), P = 8.71 × 10−3] in high severity group, with incomplete response toward antipsychotics. To our knowledge, this is the first study to identify genetic polymorphisms associated with the efficacy of antipsychotic treatment of schizophrenia patients from two major India populations.
    08/2015; DOI:10.1002/mgg3.169
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    • "Amongst these, 355 (83.92%) were on atypical monotherapy mainly risperidone (n ¼ 260; 61.45%). According to baseline 2 AMERICAN JOURNAL OF MEDICAL GENETICS PART B severity score, patients were broadly categorized into low severity (LSG; CGI-S ¼ score 3) and high severity groups (HSG; CGI-S ! 4) [Chen et al., 2009]. Leucht and Engel 2006, reported CGI may have similar sensitivity as the BPRS to evaluate various antipsychotic drugs efficacy, hence for present study we considered CGI-improvement score to evaluate response of patients towards drugs, where clinicians have critically evaluated and analyzed the every aspect of the individual before rating them on CGI for their response towards particular drug. "
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    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.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 12/2014; 165(8). DOI:10.1002/ajmg.b.32268 · 3.42 Impact Factor
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    • "Stronger predictive characteristics in this analysis may have been due to use of a later time point to assess early response; Week 4 for this analysis versus Week 2 in the oral olanzapine studies. Predictions of later response have been shown to improve as the time point for early assessment is delayed,[17]. and a balance must be struck between improved predictive accuracy and expedient recognition of a need to adjust treatment. In this instance, the later time point was chosen because for many of the patients in this study, 4 weeks represented the interval between injections, and was therefore the earliest point at which treatment could be re-evaluated. "
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    ABSTRACT: In patients with schizophrenia, early non-response to oral antipsychotic therapy robustly predicts subsequent non-response to continued treatment with the same medication. This study assessed whether early response predicted later response when using a long-acting injection (LAI) antipsychotic. Data were taken from an 8-week, randomized, double-blind, placebo-controlled study of olanzapine LAI in acutely ill patients with schizophrenia (n = 233). Early response was defined as ≥ 30% improvement from baseline to Week 4 in Positive and Negative Syndrome Scale (PANSS0-6) Total score. Subsequent response was defined as ≥ 40% baseline-to-endpoint improvement in PANSS0-6 Total score. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and predictive accuracy were calculated. Clinical and functional outcomes were compared between Early Responders and Early Non-responders. Early response/non-response to olanzapine LAI predicted later response/non-response with high sensitivity (85%), specificity (72%), PPV (78%), NPV (80%), and overall accuracy (79%). Compared to Early Non-responders, Early Responders had significantly greater improvement in PANSS0-6 Total scores at all time points and greater baseline-to-endpoint improvement in PANSS subscale scores, Quality of Life Scale scores, and Short Form-36 Health Survey scores (all p ≤ .01). Among Early Non-responders, 20% demonstrated response by Week 8. Patients who lacked early improvement (at Week 4) in Negative Symptoms and Disorganized Thoughts were more likely to continue being non-responders at Week 8. Among acutely ill patients with schizophrenia, early response predicted subsequent response to olanzapine LAI. Early Responders experienced significantly better clinical and functional outcomes than Early Non-responders. Findings are consistent with previous research on oral antipsychotics. CLINICAL TRIALS REGISTRY: F1D-MC-HGJZ: Comparison of Intramuscular Olanzapine Depot With Placebo in the Treatment of Patients With Schizophrenia identifier - NCT00088478.
    BMC Psychiatry 09/2011; 11(1):152. DOI:10.1186/1471-244X-11-152 · 2.21 Impact Factor
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