The Temporal Relationship Between Symptom Change and Treatment Discontinuation in a Pooled Analysis of 4 Schizophrenia Trials

Abstract

Treatment discontinuation is common in antipsychotic trials for the treatment of schizophrenia and is often associated with symptom worsening. This study assessed the timing and the magnitude of symptom change associated with treatment discontinuation for any cause, and whether improvement in specific symptom domains was predictive of treatment persistence. This post hoc analysis used pooled data from 1627 patients with schizophrenia spectrum disorders who were enrolled in 4 randomized, double-blind antipsychotic comparator trials of 24 to 28 weeks duration. Mean change in the Positive and Negative Syndrome Scale (PANSS) total scores during the last available visit interval were compared for patients who did and did not complete the trial. Improvements in positive, negative, and depression subscores of the PANSS were used to predict trial persistence. A total of 866 patients (53%) discontinued treatment of any cause during the studies. Patients who discontinued treatment early (weeks 0-4) had no significant improvement in mean PANSS total score during the last visit interval, whereas those who discontinued beyond week 4 had significant worsening of mean PANSS total score in the final visit interval. Improvements in either PANSS positive or depression subscores, but not in the PANSS negative subscore, were strongly predictive of study completion. These findings suggest that early failure to establish treatment response and later symptom worsening are associated with treatment discontinuation for any cause. Early improvement in positive or depressive/anxiety symptoms is especially predictive of treatment persistence.

Predictors of switching antipsychotic medications in the treatment of schizophrenia

“…Current findings are consistent with previous research demonstrating that depressive symptoms are associated with a significantly higher propensity to discontinue treatment for any cause [39-41]. The study by Kinon and colleagues [40] investigated this aspect in some detail, with a post-hoc analysis of pooled data from four antipsychotic trials for the treatment of schizophrenia (n = 1,627). That study showed that patients with a 4-point improvement in PANSS depression/anxiety subscore were significantly less likely to discontinue treatment, and an early response in depressive/anxiety symptoms was associated with a 50% greater likelihood of study completion.…”

Patient perspectives on antipsychotic treatments and their association with clinical outcomes

“…This was unexpected, because numerous studies have identified positive symptom severity as the leading predictor of higher risk of discontinuation. [31][32][33][34][35] Moreover, patient compliance 36,37 and attitude toward medication 15 have been linked to PANSS positive subscale scores. However, the depressive symptom cluster has also been implicated as an important factor in both adherence 5,32,35 and attitude toward medication, 38 as have symptoms of hostility/excitement.…”

“…[31][32][33][34][35] Moreover, patient compliance 36,37 and attitude toward medication 15 have been linked to PANSS positive subscale scores. However, the depressive symptom cluster has also been implicated as an important factor in both adherence 5,32,35 and attitude toward medication, 38 as have symptoms of hostility/excitement. 5,39 In fact, recently published data 16 show that, while the positive symptom cluster may indeed be the strongest predictor of patient attitudes and adherence, a correlation can nevertheless be found between adherence and general PANSS symptom reduction.…”

Does early improvement predict response to the fast-dissociating D2 receptor antagonist JNJ-37822681 in patients with acute schizophrenia? ☆

“…Furthermore, the ''delayed-onset hypothesis of antipsychotic action'', which suggested that 6-8 weeks are required to determine a therapy's effectiveness in patients with schizophrenia has been largely rejected (Agid et al, 2003(Agid et al, , 2006Ascher-Svanum et al, 2008;Levine and Leucht, 2010;Kinon et al, 2010b). Meta-analyses and post hoc analyses of data from randomised controlled trials in the treatment of schizophrenia have demonstrated that early nonresponse (at 1 or 2 weeks) to treatment with antipsychotic agents appears to be a robust predictor of subsequent nonresponse (Agid et al, 2003;Ascher-Svanum et al, 2008;Correll et al, 2003;Leucht et al, 2005Leucht et al, , 2007Kinon et al, 2008). Likewise, a recent study in patients with acute schizophrenia indicated that an early response (Z30% improvement from baseline in PANSS total score at week 4) to antipsychotic medication may serve as an early clinical marker that clinicians can use to balance the benefit and risk of treatment (AscherSvanum et al, 2011).…”