- Email: [email protected]
S.05.02 Early response as a response predictor: use of individual variability in clinical trials
S.05. Understanding individual variability in response - trajectories and predictors ofresponse
The 5-HTIA receptor binding potential (BPND) was quantified for manually defined DRN regions of interest using the radioligand [carbonyl-llqWAY100635 and the simplified reference tissue model. During fMRI measurements on a 3T scanner subjects completed a rewarding paradigm with attractive and unattractive faces. Multimodal regression analysis included the individual fMRI activation maps as dependent variable and 5-HTlA BPND of the DRN as regressor. Results: Within healthy subjects we found a positive association between the DRN 5-HTIA BPND and the neuronal activation in both hemispheres of the orbitofrontal cortex (r= 0.621, p = 0.0002). This relationship was not significant for the patient group (r=-0.35, p=0.322) and direct comparison between the study populations gave significant differences at the parametric level (p < 0.01). Conclusions: This study demonstrates the modulatory effect of DRN 5-HTIA autoreceptors on the orbitofrontal cortex during rewarding stimuli in healthy subjects. However, the missing significant relationship in the amygdala [3] might be related to different fMRI paradigms and data analysis. More importantly, the significantly attenuated association within the patient group possibly explains the amygdala hyperactivity in anxiety disorders [2]. References
[1] Lanzenberger, R., Mitterhauser, M., Spinde1egger, C., et aI., 2007. Reduced serotonin-1A receptor binding in social anxiety. Biological Psychiatry 61: 1081-1089. [2] Monk, C.S., Te1zer, E.H., Mogg, K., et aI., 2008. Amygdala and ventrolateral prefrontal cortex activation to masked angry faces in children and adolescents with generalized anxiety disorder. Archives of General Psychiatry 65(5): 568-576. [3] Fisher, P.M., Meltzer, C.C., Ziolko, S.K., et aI., 2006. Capacity for 5-HTlA-mediated autoregulation predicts amygdala reactivity. Nature Neuroscience 9 (11): 1362-1363.
8.05. Understanding individual variability in response - trajectories and predictors of response 18.05.011 Understanding individual variability in response: a review of the evidence
S. Leucht1 '. 1 Technische Universitiit Miinchen, Psychiatry and Psychotherapy, Munich, Germany Generally, the response to medication varies considerably. In some patients a significant improvement already appears after several hours; for other patients it can take weeks. Recent evidence refuted the long-held textbook statements that on the average the effect of antipsychotic drugs only shows up with a delay of several weeks. In a meta-analysis of 53 studies, Agid et al. 2003 [1] found that the greatest symptom reduction occurs in the first weeks and continuously declines at later stages. This finding was expanded to one year in an analysis of more than 700 individual patient data (Leucht et al. 2005 [2]), and other studies disentangled the effects of antipsychotics from those of placebo within 24 hours [3]. The new "early onset of antipsychotic drug action hypothesis" has stimulated hope that it may be possible to predict response early after initiation of treatment. A series of studies since the 1980's have shown that a degree of initial response correlates well with the degree of response after 4-6 weeks. The main limitation of these studies was that they did not provide cut-offs of a degree of initial symptom-reduction which predicts future
Sl83
response. More recent analyses tried to develop more clinically useful models. Although the individual results differed, theses analyses suggested that no to little reduction of symptoms (-less than 20-25% BPRSIPANSS total score reduction) predicts later response with sufficient specificity. References
[1] Agid 0, Kapur S, Arenovich T, et aI. Delayed-onset hypothesis of antipsychotic action - A hypothesis tested and rejected. Arch Gen Psychiatry 2003; 60: 1228-1235 [2] Leucht S, Busch R, Hamann J, et aI. Early onset of antipsychotic drug action: a hypothesis tested, confirmed and extended. BioI Psychiatry 2005;57: 1543-1549 [3] Kapur S, Arenovich T, Agid 0, et aI. Evidence for onset of antipsychotic effects within the first 24 hours of treatment. Am J Psychiatry 2005; 162: 939-946
18.05.021 Early response as a response predictor: use of individual variability in clinical trials
B.J. Kinon 1 " L. Chen1, H. Ascher-Svanum1, V. Stauffer2, 1Eli S. Kollack-Walker2, W. Zhou2 , S. Kapu.?, J. Kane4 . Lilly and Company, Lilly Corporate Center, Indianapolis IN, USA; 2Lilly USA LLG, Lilly Corporate Center, Indianapolis IN, USA; 3 Kings College ofLondon, Institute ofPsychiatry, London, United Kingdom; 4 Zucker Hillside Hospital, Psychiatry, Glen Oaks NY, USA Objectives: The primary objective of this study was to assess in a prospective manner if early response to atypical antipsychotic treatment is associated with subsequent improvement in psychopathology. This randomized, double-blind, flexible-dosed, 12-week study enrolled 630 patients diagnosed with schizophrenia or schizoaffective disorder. All patients were initially assigned to risperidone therapy, with early responder/non-responder status assessed. Early response was defined as at least minimal improvement on the Positive and Negative Syndrome Scale (PANSS) total score from baseline to 2 weeks; 17% of patients discontinued during this period. Early responders to risperidone continued with risperidone therapy (N = 144), whereas early non-responders to risperidone were randomized (1: 1) in a double-blind manner to either continue on risperidone 2-6mg/day (N= 192) or switch to olanzapine 1O-20mg/day (N = 186) for 10 additional weeks of therapy. Subsequent assessment of improvement in psychopathology was measured by PANSS total score. Early non-response to risperidone was observed in 72.4% of patients while early response was observed in 27.6%. Consistent with our hypothesis, patients who met the criterion of early response to risperidone treatment showed significantly greater improvement in symptoms at all time points measured compared to patients who did not meet this criterion. The mean reduction in PANSS total score at study endpoint was -35.1 for risperidone early responders and -18.6 for risperidone early nonresponders (LS mean change from MMRM Model; p < 0.001). Conclusion: This prospective study demonstrates that early non-response to an atypical antipsychotic (risperidone) is associated with significantly poorer subsequent improvement in psychopathology compared to early responders.
The 5-HTIA receptor binding potential (BPND) was quantified for manually defined DRN regions of interest using the radioligand [carbonyl-llqWAY100635 and the simplified reference tissue model. During fMRI measurements on a 3T scanner subjects completed a rewarding paradigm with attractive and unattractive faces. Multimodal regression analysis included the individual fMRI activation maps as dependent variable and 5-HTlA BPND of the DRN as regressor. Results: Within healthy subjects we found a positive association between the DRN 5-HTIA BPND and the neuronal activation in both hemispheres of the orbitofrontal cortex (r= 0.621, p = 0.0002). This relationship was not significant for the patient group (r=-0.35, p=0.322) and direct comparison between the study populations gave significant differences at the parametric level (p < 0.01). Conclusions: This study demonstrates the modulatory effect of DRN 5-HTIA autoreceptors on the orbitofrontal cortex during rewarding stimuli in healthy subjects. However, the missing significant relationship in the amygdala [3] might be related to different fMRI paradigms and data analysis. More importantly, the significantly attenuated association within the patient group possibly explains the amygdala hyperactivity in anxiety disorders [2]. References
[1] Lanzenberger, R., Mitterhauser, M., Spinde1egger, C., et aI., 2007. Reduced serotonin-1A receptor binding in social anxiety. Biological Psychiatry 61: 1081-1089. [2] Monk, C.S., Te1zer, E.H., Mogg, K., et aI., 2008. Amygdala and ventrolateral prefrontal cortex activation to masked angry faces in children and adolescents with generalized anxiety disorder. Archives of General Psychiatry 65(5): 568-576. [3] Fisher, P.M., Meltzer, C.C., Ziolko, S.K., et aI., 2006. Capacity for 5-HTlA-mediated autoregulation predicts amygdala reactivity. Nature Neuroscience 9 (11): 1362-1363.
8.05. Understanding individual variability in response - trajectories and predictors of response 18.05.011 Understanding individual variability in response: a review of the evidence
S. Leucht1 '. 1 Technische Universitiit Miinchen, Psychiatry and Psychotherapy, Munich, Germany Generally, the response to medication varies considerably. In some patients a significant improvement already appears after several hours; for other patients it can take weeks. Recent evidence refuted the long-held textbook statements that on the average the effect of antipsychotic drugs only shows up with a delay of several weeks. In a meta-analysis of 53 studies, Agid et al. 2003 [1] found that the greatest symptom reduction occurs in the first weeks and continuously declines at later stages. This finding was expanded to one year in an analysis of more than 700 individual patient data (Leucht et al. 2005 [2]), and other studies disentangled the effects of antipsychotics from those of placebo within 24 hours [3]. The new "early onset of antipsychotic drug action hypothesis" has stimulated hope that it may be possible to predict response early after initiation of treatment. A series of studies since the 1980's have shown that a degree of initial response correlates well with the degree of response after 4-6 weeks. The main limitation of these studies was that they did not provide cut-offs of a degree of initial symptom-reduction which predicts future
Sl83
response. More recent analyses tried to develop more clinically useful models. Although the individual results differed, theses analyses suggested that no to little reduction of symptoms (-less than 20-25% BPRSIPANSS total score reduction) predicts later response with sufficient specificity. References
[1] Agid 0, Kapur S, Arenovich T, et aI. Delayed-onset hypothesis of antipsychotic action - A hypothesis tested and rejected. Arch Gen Psychiatry 2003; 60: 1228-1235 [2] Leucht S, Busch R, Hamann J, et aI. Early onset of antipsychotic drug action: a hypothesis tested, confirmed and extended. BioI Psychiatry 2005;57: 1543-1549 [3] Kapur S, Arenovich T, Agid 0, et aI. Evidence for onset of antipsychotic effects within the first 24 hours of treatment. Am J Psychiatry 2005; 162: 939-946
18.05.021 Early response as a response predictor: use of individual variability in clinical trials
B.J. Kinon 1 " L. Chen1, H. Ascher-Svanum1, V. Stauffer2, 1Eli S. Kollack-Walker2, W. Zhou2 , S. Kapu.?, J. Kane4 . Lilly and Company, Lilly Corporate Center, Indianapolis IN, USA; 2Lilly USA LLG, Lilly Corporate Center, Indianapolis IN, USA; 3 Kings College ofLondon, Institute ofPsychiatry, London, United Kingdom; 4 Zucker Hillside Hospital, Psychiatry, Glen Oaks NY, USA Objectives: The primary objective of this study was to assess in a prospective manner if early response to atypical antipsychotic treatment is associated with subsequent improvement in psychopathology. This randomized, double-blind, flexible-dosed, 12-week study enrolled 630 patients diagnosed with schizophrenia or schizoaffective disorder. All patients were initially assigned to risperidone therapy, with early responder/non-responder status assessed. Early response was defined as at least minimal improvement on the Positive and Negative Syndrome Scale (PANSS) total score from baseline to 2 weeks; 17% of patients discontinued during this period. Early responders to risperidone continued with risperidone therapy (N = 144), whereas early non-responders to risperidone were randomized (1: 1) in a double-blind manner to either continue on risperidone 2-6mg/day (N= 192) or switch to olanzapine 1O-20mg/day (N = 186) for 10 additional weeks of therapy. Subsequent assessment of improvement in psychopathology was measured by PANSS total score. Early non-response to risperidone was observed in 72.4% of patients while early response was observed in 27.6%. Consistent with our hypothesis, patients who met the criterion of early response to risperidone treatment showed significantly greater improvement in symptoms at all time points measured compared to patients who did not meet this criterion. The mean reduction in PANSS total score at study endpoint was -35.1 for risperidone early responders and -18.6 for risperidone early nonresponders (LS mean change from MMRM Model; p < 0.001). Conclusion: This prospective study demonstrates that early non-response to an atypical antipsychotic (risperidone) is associated with significantly poorer subsequent improvement in psychopathology compared to early responders.