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Characteristics of two alternative schizophrenia remission definitions: Relationship to clinical and quality of life outcomes
Schizophrenia Research 86 (2006) 300 – 308 www.elsevier.com/locate/schres
Characteristics of two alternative schizophrenia remission definitions: Relationship to clinical and quality of life outcomes Eduardo Dunayevich ⁎, Gopalan Sethuraman, Mark Enerson, Cindy C. Taylor, Daniel Lin Lilly Research Laboratories, Indianapolis, IN, 46285, USA Received 9 November 2005; received in revised form 31 May 2006; accepted 5 June 2006 Available online 24 July 2006
Abstract Background: The goal of these secondary analyses of clinical trial data was to characterize clinical outcomes in patients with schizophrenia who met symptom severity or duration thresholds for two alternative definitions of remission, and to explore their relationships to improvement duration and quality of life outcomes. Methods: Definition 1 used threshold criteria for selected PANSS items sustained over at least 6-months Definition 2 used Brief Psychiatric Rating Scale (BPRS) % change, a threshold score for the Clinical Global Improvement-Severity (CGI-S) maintained for at least 8 weeks, and threshold scores for selected BPRS items. Positive and Negative Symptom Scale (PANSS) and Quality of Life scale (QLS) total scores were pooled from 6 clinical trials. The extent to which the alternative severity thresholds from these two definitions and duration of clinical improvement were associated with different clinical and QLS outcomes was explored. Regression analysis also assessed the relative contribution of each of the components of the two definition severity thresholds to improvements in QLS Total score. Results: Increases in QLS scores were greater for those patients who met either threshold criteria relative to those who met neither (p < .0001). Significantly greater improvements in QLS scores were observed for patients who met either threshold criteria at the 8-, 16- and 24-week visits relative to those who met criteria at weeks 16 and 24, or at week 24 only (p < 0.001), as well as for the subset of patients who met threshold criteria at both 24 and 52 weeks relative to those who met criteria at only one of these 2 time points. Only 31% to 47% of patients meeting threshold criteria for either definition at the 8-, 16- or 24-week visits remained in remission at the 52-week visit. Among the severity threshold components analyzed, BPRS total % change from baseline was the strongest predictor of improvement in QLS scores. Conclusions: Quality of life improved most for patients who achieved severity thresholds associated with either remission criteria and who stayed improved for longer periods. Total BPRS change scores accounted for the greatest percentage of the QLS scores variance. Only a fraction of patients who meet severity criteria for either remission definition early in treatment will remain at that level of improvement within the subsequent 9–12 months. © 2006 Elsevier B.V. All rights reserved. Keywords: Schizophrenia; Meta-analysis; Remission; Quality of life; Antipsychotics; Functional outcomes
1. Introduction ⁎ Corresponding author. Tel.: +1 317 651 2602; fax: +1 317 277 6896. E-mail address: [email protected] (E. Dunayevich). 0920-9964/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2006.06.002
There has been a recent initiative to establish consensus on criteria defining remission in schizophrenia (Andreasen et al., 2005). A broadly accepted
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remission definition would assist in establishing standards for adequate care, facilitating meaningful comparisons between therapeutic agents, and for use in the development of novel therapeutics. Current conceptualizations of remission are based on the assumption that in schizophrenia, as in other psychiatric disorders such as depression and anxiety, a clinical severity threshold can be defined that reflects a relative absence of the hallmark symptoms of the disorder. In a recent analysis of a clinical trial comparing olanzapine with risperidone in patients with schizophrenia, differences in outcomes between treatment groups with respect to duration of time in remission were observed when elements of two proposed definitions of remission were applied (Breier et al., 2003; Sethuraman et al., 2005). These findings underscore the potential utility of remission definitions and how they may relate to outcomes in schizophrenia. Thus far, proposed criteria for remission have focused predominantly on establishing clinical severity thresholds using some of the assessment tools currently available for the evaluation of symptoms, such as the Positive and Negative Symptom Scale (PANSS) or the Brief Psychiatric Rating Scale (BPRS). Minimal duration of maintaining clinical severity threshold requirements have also been proposed. However, empirical evidence supporting clinical and duration requirements has been limited to date (Lieberman et al., 2003; Andreasen et al., 2005). Additionally, Quality of Life (QOL) measures, while not usually included in the proposed definitions of remission, have also become important indicators of outcome: Double-blind clinical studies have demonstrated QOL improvement during antipsychotic treatment (Hamilton et al., 1998, 2000; Marder et al., 2003; Revicki et al., 1999). Significant correlations have been demonstrated between QOL and the severity of symptoms in schizophrenia (BowThomas et al., 1999; Breier et al., 1991; Mueser et al., 1991); and schizophrenia patients who attain symptomatic remission over the course of antipsychotic treatment are likely to experience greater improvements in QOL than those who do not. The goal of the secondary analyses of pooled clinical trial data presented in this manuscript was to explore the characteristics of patients who met clinical severity or duration thresholds for two alternative definitions of remission (Andreasen et al., 2005; Lieberman et al., 2003) and the relationship of these thresholds to QOL outcomes. These definitions were especially useful for the purposes of comparison as they were dissimilar in several ways: One was intended for recent-onset or acute schizophrenia, used clinical rating change total scores as one of its main components, and established a
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minimum duration criterion of 8 weeks (Lieberman et al., 2003), while the other was intended for chronic schizophrenia, used absolute severity thresholds, and a minimum duration requirement of 6 months (Andreasen et al., 2005). More specifically, we aimed to examine, 1. If patients achieving either of these alternative severity thresholds differed meaningfully from those patients who did not reach them in clinical and QOL ratings; 2. Whether meeting alternative severity thresholds is associated with different degrees of clinical and QOL improvement. 3. Which elements of these alternative severity thresholds accounted for the greatest degree of variance in QOL outcomes; 4. If a longer time displaying improvement consistent with either threshold was associated with varying degrees of QOL improvement; 5. The effects of applying increasingly greater duration requirements on the predictive value of these clinical severity thresholds. 2. Methods 2.1. Patient population and study design The present post hoc analyses used pooled data derived from 6 double-blind, randomized, multicenter clinical trials, comparing olanzapine with other antipsychotic drugs: vs. risperidone (N = 339, Tran et al., 1997, vs. ziprasidone (N = 944, Breier et al., 2005; N = 394, Kinon et al., 2006), vs. quetiapine (N = 347, Kinon et al., 2003), vs. haloperidol (N = 1996, Tollefson et al., 1997), and vs. haloperidol and risperidone (N = 414, Breier et al., 2003). Complete details and primary results of these clinical trials are reported elsewhere. Briefly, the subjects were inpatients or outpatients, either sex, aged 18–75 years with a diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder (DSM-IV). To be included in the present analyses, patients had to have a baseline value and one subsequent QOL assessment. The Breier et al. (2003) study enrolled a population of relatively stable schizophrenic patients, the Kinon et al. (2003) study enrolled patients with predominant negative symptoms, and the Kinon et al. (2006) study enrolled patients with prominent depressive symptoms; the other 3 studies enrolled patients who were experiencing an acute exacerbation of psychotic symptoms. Four studies were 6 months in duration of blinded therapy, two (Tollefson et al., 1997; Breier et al., 2003) were longer (24 and 12 months, respectively). Observations from the subset of patients who participated in these 2 longer studies for up to 12 months were pooled for exploratory analyses on the effects of time on QLS scores, and to
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assess proportion of patients meeting threshold criteria at the week 8, 16 or 24 timepoints who continued to meet criteria at the 52 week timepoint. 2.2. Definitions of clinical severity threshold criteria Clinical severity thresholds from 2 alternative definitions of remission were used for the present analyses. Definition 1 was developed by an expert consensus panel and required that a patient achieve scores of no greater than 3 (mild) concurrently on each of the following PANSS items: delusions, conceptual disorganization, hallucinatory behavior, blunted affect, passive/apathetic social withdrawal, lack of spontaneity and conversation flow, mannerisms and posturing, and unusual thought content (Andreasen et al., 2005). The panel also suggested that a patient maintain this level of symptom severity for a minimum of 6 months. Definition 2, which was proposed by Lieberman et al. (2003), required that a patient achieve 50% reduction in BPRS Total score from baseline, scores of ≤3 concurrently on each of the BPRS psychosis items (unusual thought content, suspiciousness, hallucinations, conceptual disorganization, mannerisms and posturing), and Clinical Global Impressions-Severity (CGI-S) score ≤ 3 for a minimum of 8 weeks. (Note: CGI-S scores were not collected in two of the six studies used in this pooled analysis (Kinon et al., 2006). A criteria of CGI-I ≤ 2 (much improved to very much improved) was used in place of CGI-S in those cases, except in regression analyses were only CGI-S data was used). 2.3. Statistical methods At each timepoint (8, 16, and 24 weeks), patients were grouped according to whether they met clinical severity threshold for 1.) Definition 1 criteria, but not Definition 2 criteria (Definition 1 exclusive); 2.) Definition 1 criteria including those who also met Definition 2 criteria (Definition 1 inclusive); 3.) Definition 2 criteria including those who also met Definition 1 criteria (Definition 2 inclusive); 4.) Definition 2 criteria excluding those who also met Definition 1 criteria (Definition 2 exclusive); 5) Either Definition 1 or Definition 2 severity criteria (Either); or 6.) Neither criteria (Neither). Overall group assignments were determined based on whether a patient met either severity threshold criteria at any time point (neither vs. either); for those that met severity threshold criteria, it was determined by which threshold(s) they met at any time in the study. The baseline and demographic characteristics were compared between groups using ANOVA with contrasts
of pair-wise comparisons for the continuous variables (age, age of onset, duration of illness, baseline PANSS total score, baseline QLS total score, number of prior hospitalizations, length of stay in hospital), or Fisher's exact test for categorical variables (gender, ethnicity [Caucasian vs. all others]). An ANCOVA model was used to analyze mean PANSS Total score changes from baseline at the 8-, 16-, and 24-week endpoints. The model included the severity group as the sole independent variable, with baseline PANSS as a continuous covariable. Severity groups were compared against the Neither group with contrasts using the Student–Newman–Keuls method from the ANCOVA model (Other comparisons between severity groups could not be performed due to overlaps in group membership). To facilitate comparisons across all groups, estimates of effect size on PANSS total score were also calculated relative to the Neither group. Due to change in group membership from timepoint to timepoint, the change scores were calculated separately for each of the 8-, 16-, and 24-week endpoints. Similar analyses of mean QLS Total score changes from baseline at 8-, 16-, and 24-week and 52 week endpoints were performed according to the above severity groupings, using an ANCOVA model to compare the dependent variable of QLS change scores. The model included the severity group as an independent class variable along with the baseline QLS score as a continuous covariable. Severity threshold groups were compared against the Neither group with contrasts using the Student–Newman–Keuls method from the ANCOVA model (Other comparisons could not be performed due to the overlaps in group membership). To facilitate comparisons across all groups, estimates of effect size on QLS change scores were also calculated for the severity groups relative to the Neither group. Due to change in group membership from timepoint to timepoint, the change scores were calculated separately for each of the 8-, 16-, and 24-week endpoints. To assess the contribution of the different elements constituting the severity thresholds for Definition 1 and Definition 2 to QLS change scores, BPRS total % change from baseline, CGI-S scores (from the 4 studies where CGI S data was available) and the combined 8 items of the PANSS that were included in the Definition 1 severity threshold were analyzed using stepwise regression analysis. To assess the impact of time meeting severity criteria on QOL measures, the following analyses were performed: 1) A comparison of mean QLS total score change from baseline to week 8, week 16 and week 24 for patients using a repeated measures mixed model
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ANCOVA to compare the dependent variable of QLS change scores. The model included the clinical severity groups “Either” or “Neither” as the independent class variable along, baseline QLS score as a continuous covariable, and patients as a random effect. The covariance structure of the R matrix in the model was set to the default structure of variance components. The analyses were performed separately for the groups that met or did not meet severity threshold (i) at week 8, week 16 and week 24, (ii) week 16 and week 24 but not week 8, (iii) week 24 but not week 8 and 16. To assess time effects on QLS beyond 24 weeks across severity threshold groups, the data from patients in the Tollefson et al. (1997) and Breier et al. (2003) studies who completed at least 12 months of study participation was fitted to an ANCOVA model to compare the mean QLS Total score change from baseline to week 24 and week 52 between the “either” and “neither” improvement groups. The model included the clinical severity groups “Either” or “Neither” as the independent class variable and baseline QLS score as a continuous covariable. Lastly, to further explore what timepoints after initiating therapy may be most indicative of a sustained clinical response (in this case, defined as maintaining Definition 1 or Definition 2 severity threshold at the 52 week timepoint), we calculated the proportion of patients from the Tollefson et al. (1997) and Breier et al. (2003) studies who met severity thresholds at the week 8, 16 and 24 timepoints and continued to meet severity threshold criteria at the week 52 timepoint.
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All statistical analyses was done using the SAS© version 8.2 (Cary, NC). 3. Results Out of 3626 randomized patients, 2771 (76%) had baseline values and at least 1 subsequent QOL assessment. Of the 2771 patients included in the present analyses, 50.1% (N = 1389) completed 6 months of blinded study therapy. Over the 6-month period where all 6 studies contributed data, discontinuation due to adverse events occurred in 11.1% of patients, 10.4% discontinued due to lack of efficacy as perceived by the patient, physician or both, with the remainder of discontinuations (28.6%) due to “other” reasons. “Other” reasons included patient conflict or decision, lost to follow-up, protocol violation, physician decision, noncompliance, protocol entry criteria not met, protocol variance, sponsor decision, moved away, protocol interim criteria not met, and satisfactory response. The proportion of patients who met either improvement threshold criteria at any time during the 6-month analysis period was 65.9% (N = 1825). All but 70 patients meeting Definition 2 clinical severity criteria also met Definition 1 criteria. As such, Definition 1 inclusive became essentially synonymous with “all patients who met criteria for either definition”. Due to the small sample size relative to the Either group (< 5%), no further separate analyses were performed for the Definition 2 exclusive group. Baseline characteristics for patients included in the present analyses are shown
Table 1 Baseline patient characteristics by severity group a Characteristic
Neither (N = 608)
Either b (N = 1825)
Definition 1 exclusive (N = 902)
Definition 2 inclusive c (N = 923)
Neither + Either (N = 2433)
No baseline and/ or post-baseline QLS (N = 920)
Age, years Male, N (%) Caucasian, N (%) Age of onset, years PANSS total score PANSS positive score PANSS negative score QLS total score No. of hospitalizations Hospital. duration, days Illness duration, years
39.7 ± 11.1 438 (72.0) 382 (62.8) 23.1 ± 7.9 93.9 ± 18.7 22.0 ± 6.0 25.7 ± 6.4 46.0 ± 19.8 1.1 ± 1.0 18.8 ± 42.1 16.5 ± 10.2
39.1 ± 10.5 1182 (64.8) ⁎ 1118 (61.3) 23.6 ± 7.9 86.1 ± 18.2 ⁎ 20.4 ± 5.7 ⁎ 22.7 ± 6.2 ⁎ 56.2 ± 20.8 ⁎ 0.8 ± 0.9 ⁎ 17.3 ± 43.1 15.5 ± 10.1 ⁎
40.3 ± 9.9 593 (65.7) ⁎ 521 (57.8) 23.5 ± 7.6 82.9 ± 17.0 ⁎ 19.4 ± 5.5 ⁎ 21.8 ± 6.0 ⁎ 57.1 ± 20.1 ⁎ 0.7 ± 1.0 ⁎ 25.3 ± 63.8 16.8 ± 9.7
38.0 ± 11.0 ⁎ 589 (63.8) ⁎ 597 (64.7) 23.8 ± 7.9 89.2 ± 18.8 ⁎ 21.5 ± 5.7 ⁎ 23.5 ± 6.3 ⁎ 55.4 ± 21.4 ⁎ 0.9 ± 0.9 ⁎ 13.4 ± 27.4 14.2 ± 10.0 ⁎
39.3 + 10.7 1620 (66.6) 1500 (61.7) 23.5 + 7.9 88.0 + 18.4 20.8 + 5.8 23.4 + 6.3
38.6 + 11.1 ⁎⁎ 586 (63.7) 674 (73.3) 23.8 + 7.7 92.8 + 19.7 ⁎⁎ 22.03 + 6.2 ⁎⁎ 24.6 + 6.9 ⁎⁎
0.9 + 0.9 17.7 + 42.7 15.7 + 10.1
1.4 + 1.0 ⁎⁎ 41.2 ± 64.3 ⁎⁎ 14.8 + 10.5 ⁎⁎
a
Reported as mean ± S.D. unless otherwise indicated. Baseline characteristics for the Definition 1 inclusive group were similar to the "Either" group; only 70 patients from the Definition 2 group were not part of the Definition 1 inclusive group. c Includes patients who also met Definition 1 criteria. ⁎ p < 0.05 vs Neither. ⁎⁎ p < 0.05 vs. Neither + Either. b
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in Table 1. There were 2410 total patients randomized in the two studies combined. Of these 1421 (59%) patients had one post-baseline QLS measurement. 502 patients (21%) completed 52 weeks of the study and had a QLS measurement at week 52. On the basis of the severity threshold criteria groupings, mean baseline PANSS Total, and Positive and Negative symptom subscale scores were significantly higher in patients in the Neither group relative to those in the Either group. The Neither group also had a significantly lower (10 points) mean baseline QLS Total score relative to the Either group, consisted of a higher proportion of males, a longer duration of illness, and a greater number of previous hospitalizations. The absolute number of patients meeting either of these severity threshold criteria decreased over time, however the proportion of patients meeting these thresholds increased due to greater patient attrition in the “Neither” group. (Fig. 1). Decreases in mean PANSS Total, Positive and Negative scores from baseline were significantly greater at all time points for all groups relative to the Neither group (p < 0.0001) (Fig. 2). The mean reductions in PANSS Total score (and corresponding effect sizes) at week 24 were − 21.7 (E.S. 0.4) for Definition 1
Fig. 1. Visit-wise proportion of patients meeting severity threshold criteria.
Fig. 2. Visit-wise PANSS Total scores for the different severity groups.
exclusive, − 33.9 (E.S. 1.0) for Definition 1 inclusive, and − 42.6 (E.S. 1.6) for Definition 2 inclusive groups. Mean changes from baseline in QLS Total score across visits (Fig. 3) were significantly greater at all time points for all groups relative to the Neither group (all p < 0.0001). At week 24, mean changes in QLS Total score from baseline, and associated effect sizes relative to the Neither group, were 8.9 ± 17.8 (n = 323) (E.S. 0.31) for Definition 1 exclusive, 15.4 ± 20.6 (n = 719) (E. S. 0.63) for Definition 1 inclusive, and 19.6 ± 20.9 (n = 456) (E.S. 0.87) for Definition 2 inclusive. The change from baseline for the Neither groups was 3.8 ± 15.8 (n = 610). The results of the stepwise regression analysis indicate that the BPRS total % change from baseline accounted for 15–22% of the variance between weeks 8–24, CGI-S scores (from the 4 studies where CGI S data was available) accounted for 2–3%. The aggregate of the 8 items of the PANSS included in Definition 1 severity threshold did not account for significant QLS variance at any time between weeks 8–24. Patients who reached severity threshold criteria for either Definition 1 or Definition 2 earliest and then sustained improvement meeting (and thus spent the longest time meeting criteria for either threshold) experienced significantly greater improvements in
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Table 2b Mean change from baseline in QLS total scores for patients meeting severity threshold criteria at both weeks 24 and 52 by severity group
Fig. 3. Visit-wise QLS total score mean change by severity group.
QLS Total score at week 24 relative to those who reached the threshold at either week 16 or only at week 24 (QLS change scores of 17.6 for those who met threshold at 8, 16 and 24 weeks (N = 514), vs. 12.6 for those meeting threshold at only 16 and 24 weeks (N = 114), and 6.4 for those meeting either threshold at 24 weeks only (N = 73), p <0.001). Among patients who met either threshold at all visits, QLS Total scores increased significantly across visits (12.0, 16.0, and 17.6 at 8, 16 and 24 weeks, respectively, p < 0.001). In the 12-month completer subset, similar findings of greater gains in QLS scores for patients who met the severity threshold for either definition longest, in this case at both weeks 24 and 52, were noted compared to patients who only reached severity threshold for either definition only at week 24 or only at week 52 (Table 2a). The QLS scores between patients who met threshold Table 2a Mean change from baseline in QLS total scores based on meeting severity threshold criteria Met threshold at week 24
Met threshold at week 52
Mean change from baseline in QLS Total Score
Yes No Yes
Yes Yes No
Week 24 9.6 9.1 5.2
Week 52 14.9 6.9 11.9
Severity group
QLS total scores, week 24
QLS total scores, week 52
Definition 1 inclusive (N = 160) Definition 2 inclusive (N = 113) Neither (N = 149)
10.4
16.1
12.5
18.8
3.8
3.9
criteria for Definition 1 inclusive or Definition 2 inclusive at both week 24 and week 52 timepoints appeared comparable (Table 2b). In the 12-month subset, the proportion of patients who met threshold criteria for either Definition 1 inclusive or Definition 2 inclusive at week 52 relative to all the patients meeting these criteria at earlier timepoints increased over time: 137/433 (31%), 139/358 (38%) and 160/334 (47%) of Definition 1 inclusive patients, as well as 96/297 (32%), 97/250 (38%) and 113/238 (47%) of Definition 2 patients at weeks 8, 16 and 24, respectively, were still meeting threshold criteria at week 52. 4. Discussion In these secondary analyses of pooled data from 6 clinical trials, comparisons between two clinical severity thresholds used in alternative definitions of remission indicated that the severity threshold for Definition 2, proposed by Lieberman et al. (2003), appeared more stringent than the threshold set for definition 1 (Andreasen et al., 2005), as almost all patients achieving the Definition 2 threshold also achieved the Definition 1 threshold, while the converse was not apparent. The smaller number of patients achieving the Definition 2 severity threshold experienced numerically greater mean improvements in PANSS and QLS total scores than those achieving the Definition 1 severity threshold. While no statistical testing could be performed between these groups due to overlapping membership, the greater effect sizes calculated on PANSS and QLS total change scores for the Definition 2 inclusive compared to Definition 1 inclusive, with the smallest effect sizes for the Definition 1 exclusive lend further support to this observation. As QLS total scores were sensitive to degree of improvement achieved by the different severity groups, we assessed the magnitude of the effect of constituting elements of these definitions' severity threshold on QLS scores by means of a regression analysis. In this dataset
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of mostly acutely ill patients, BPRS change scores accounted for the greatest effect on QLS total scores variance. This finding appeared consistent with the higher level of stringency of the Definition 2 severity threshold manifested in this sample. To what extent these differences in remission severity threshold may be clinically meaningful becomes more apparent when the effects of time are factored in. Only about 1/3 (8 weeks after initiating study therapy) to less than 1/2 of the patients meeting either of these severity thresholds (24 weeks after study initiation) maintained this level of improvement at the one-year time point. It appears that meeting either of these severity thresholds by themselves holds limited utility in predicting the patients who will sustain improvement at later timepoints. In these analyses, longer duration of sustained improvement identified an increasingly larger fraction of patients who would be in remission at the 52-week timepoint. While specific cutoffs were not explored, our findings suggest that a relatively stringent duration criteria may be a useful element of a remission definition. Improvements over time in Quality of Life scores were the greatest for the group of patients who met the severity threshold for greater than 6 months. While this finding is also supportive of stringent time requirements in a remission definition such as the one proposed by Andreasen et al. (2005), it is confounded by speed of improvement onset: The patients who achieved either severity threshold at the 8-week timepoint and then sustained it for the following 16 weeks were the ones who experienced the greatest gains in QLS scores. Indeed, most (160/237, 77%) of the patients who remained in remission by either criteria at week 52 had already crossed the severity threshold at week 8. In other words, while reaching clinical severity threshold for remission rapidly is no guarantee of remaining in remission, those who improve slowly are less likely to achieve sustained remission, at least if no changes in clinical management are instituted. A more encouraging finding is the observation that, for those patients who maintain clinical improvement (as indicated by sustained achievement of severity threshold criteria) QLS scores continue to improve up to the 52 week timepoint. While this may be a small subset of this large pooled dataset, the findings indicate that, at least for some patients, gradual improvement of function in the setting of sustained clinical improvement beyond the acute treatment period may be possible. The interpretation of these findings needs to be tempered by several limitations of these analyses. First, more than 50% of the initial randomized sample had discontinued study participation at the 6 month endpoint, and the patients with data beyond 6 months of
study participation were only a fraction of the entire dataset. While high levels of study discontinuation are common in schizophrenia clinical trials, the high degree of attrition reported here may have biased the findings reported here, especially because our analyses were on the subset of patients who provided at least one QLS measure after the baseline assessment. It is noteworthy that a greater proportion of patients discontinuing the study between weeks 8 and 24 were from the Neither group, consistent with reports indicating that lack of efficacy is an important driver of study discontinuation (Liu-Seifert et al., 2005). Thus it is possible that the subset that provided post-baseline measures may have experienced overall better outcomes than the patients who did not. Second, the limited period encompassed by our analyses does not allow to adequately disentangle the effects of duration of remission from speed of improvement on QLS. In other words, the effects of longer time meeting improvement criteria on QLS scores could be due to the cumulative beneficial effects of sustained improvement on QLS or that the longer time meeting threshold criteria mainly identifies patients with faster treatment response and better outcomes who consequently remained in an improved state for a longer proportion of the observation periods considered here. Additionally, as these analyses encompassed only a 6- to 12-month period, they may have inappropriately allocated to the Neither group patients who may have experienced sufficient improvement to meet threshold criteria at a later time point. Such patients, however, are likely to be few. It should also be noted that there were significant differences in baseline PANSS and QLS Total scores between non-improvers and improvers, consistent with the notion that greater illness severity and chronicity is associated with lower likelihood of achieving remission (Lasser et al., 2005). Lastly, different results may have been obtained if these analyses had been run in a sample of primarily subacute or chronic patients. Under those circumstances, it is entirely possible that only limited change may have been observed over time for PANSS and QLS scores, or that the severity threshold for Definition 1 may have been more stringent than for Definition 2. While this large dataset of pooled clinical trial patients encompasses patients with a range of baseline characteristics (including patients with symptoms of acute exacerbation as well as more stable and also patients with predominantly depressed symptoms) that suggests the findings could be generalized to other schizophrenia populations, pooling of data may also create additional confounders. Thus, caution in the interpretation of the findings reported here is warranted.
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Overall, our findings support the notion that a relatively extended longitudinal component should be integral to remission criteria. Only a minority of patients who meet remission severity thresholds early in the course of treatment sustain the clinical improvement at later timepoints. Moreover, quality of life scores improved progressively with increasing time remaining improved, regardless of threshold used, and the greatest QOL improvements were observed in patients with the earliest and longest time remaining improved. These findings are consistent with the view that, for some patients who experience sustained clinical improvement, the benefits of antipsychotic treatment on functional outcomes may accrue beyond the initial, acute treatment period (Dunayevich et al., 2005). Our findings provide only limited support to the notion that differences in the severity thresholds of Definition 1 and Definition 2 are clinically meaningful. The greater support found in our results for a relatively stringent duration threshold may simply reflect that longer time remaining in therapy, as suggested by the CATIE study results (Lieberman et al. 2005) may be one of the most important prognostic factors in the treatment of schizophrenia. In summary, the present findings examine the impact of different clinical severity and duration of improvement thresholds on the number of patients participating in clinical trials who achieve these thresholds, and the degree of clinical and QLS improvement they evidenced. Since a goal of establishing improvement and remission criteria is to define outcomes that are predictive of eventual functional recovery, definitions that encompass a concurrent and sustained resolution of symptoms as well as greater improvements in quality of life may have greater validity and practical utility. Elements from each of the remission criteria considered here, such as change scores and duration requirements, may be useful to characterize treatment outcomes, and further refinements to the composition of remission definitions may improve their utility. As proposed by Andreasen et al. (2005) additional prospective analyses in long-term studies to further examine alternative remission criteria and their relevance to quality of life and functional outcomes are needed. References Andreasen, N.C., Carpenter Jr., W.T., Kane, J.M., Lasser, R.A., Marder, S.R., Weinberger, D.R., 2005. Remission in schizophrenia: proposed criteria and rationale for consensus. Am. J. Psychiatry 162 (3), 441–449. Bow-Thomas, C.C., Velligan, D.I., Miller, A.L., Olsen, J., 1999. Predicting quality of life from symptomatology in schizophrenia at exacerbation and stabilization. Psychiatry Res. 86 (2), 131–142.
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Breier, A., Schreiber, J.L., Dyer, J., Pickar, D., 1991. National Institute of Mental Health longitudinal study of chronic schizophrenia. prognosis and predictors of outcome. Arch. Gen. Psychiatry 48 (3), 239–246. Breier, A., Young, C., Purdon, S.E., Gold, J.M., Davis, K.L., Keefe, R. S.E., 2003. A one-year double-blind comparison of the neurocognitive efficacy of olanzaine, risperidone, and haloperidol in patients with schizophrenia. Schizophr Res. 60 (1S), 274–275. Breier, A., Berg, P., Thakore, J.H., Naber, D., Gattaz, W.F., Cavazzoni, P., Walker, D.J., Roychowdhury, S.M., Kane, J.M., 2005. Olanzapine versus ziprasidone: results of the 28-week doubleblind study in Patients With Schizophrenia. Am. J. Psych. 162 (10), 1879–1887. Dunayevich, E., Zhao, F., Ascher-Svanum, A., Mitchell, C.P., Phillips, G.A., Dellva, M.A., Green, A., 2005. Longer time to all-cause antipsychotic discontinuation is associated with better schizophrenia treatment outcomes. Biol. Psychiatry 57, 107S. Hamilton, S.H., Revicki, D.A., Genduso, L.A., Beasley Jr., C.M., 1998. Olanzapine versus placebo and haloperidol: quality of life and efficacy results of the North American double-blind trial. Neuropsychopharmacology 18 (1), 41–49. Hamilton, S.H., Edgell, E.T., Revicki, D.A., Breier, A., 2000. Functional outcomes in schizophrenia: a comparison of olanzapine and haloperidol in a European sample. Int. Clin. Psychopharmacol. 15 (5), 245–255. Kinon, B., et al., 2003. Superiority of olanzapine versus quetiapine in improving overall functioning in schizophrenic patients with prominent negative symptoms. Biol. Psychiatry 53 (25S) (Suppl. Ref Type: Generic). Kinon, B.J., Lipkovich, I., Edwards, S.B., Ascher-Svanum, H., Siris, S.G., 2006. A 24-week randomized study of olanzapine versus ziprasidone in the treatment of schizophrenia or schizoaffective disorder in patients with prominent depressive symptoms. J. Clin. Psychopharmacol. 26 (2), 157–162. Lasser, R.A., Bossie, C.A., Gharabawi, G.M., Kane, J.M., 2005. Remission in schizophrenia: results from a 1-year study of long-acting risperidone injection. Schizophr. Res. 77 (2–3), 215–227. Lieberman, J.A., Phillips, M., Gu, H., Stroup, S., Zhang, P., Kong, L., Ji, Z., Koch, G., Hamer, R.M., 2003. Atypical and conventional antipsychotic drugs in treatment-naive first-episode schizophrenia: a 52-week randomized trial of clozapine vs chlorpromazine. Neuropsychopharmacology 28 (5), 995–1003. Lieberman, J.A., Stroup, T.S., McEvoy, J.P., Swartz, M.S., Rosenheck, R.A., Perkins, D.O., et al., 2005. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N. Engl. J. Med. 353 (12), 1209–1223. Liu-Seifert, H., Adams, D.H., Kinon, B.J., 2005. Discontinuation of treatment of schizophrenic patients is driven by poor symptom response: a pooled post-hoc analysis of four atypical antipsychotic drugs. BMC Med. 3, 21. Marder, S.R., Glynn, S.M., Wirshing, W.C., Wirshing, D.A., Ross, D., Widmark, C., Mintz, J., Liberman, R.P., Blair, K.E., 2003. Maintenance treatment of schizophrenia with risperidone or haloperidol: 2-year outcomes. Am. J. Psychiatry 160 (8), 1405–1412. Mueser, K.T., Douglas, M.S., Bellack, A.S., Morrison, R.L., 1991. Assessment of enduring deficit and negative symptom subtypes in schizophrenia. Schizophr. Bull. 17 (4), 565–582. Revicki, D.A., Genduso, L.A., Hamilton, S.H., Ganoczy, D., Beasley Jr., C.M., 1999. Olanzapine versus haloperidol in the treatment of schizophrenia and other psychotic disorders: quality
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of life and clinical outcomes of a randomized clinical trial. Qual. Life Res. 8 (5), 417–426. Sethuraman, G., Taylor, C.C., Enerson, M., Dunayevich, E., 2005. A retrospective comparison of cumulative time spent in remission during treatment with olanzapine or risperidone among patients with schizophrenia. Schizophr. Res. 79 (2–3), 337–340. Tollefson, G.D., Beasley Jr., C.M., Tran, P.V., Street, J.S., Krueger, J.A., Tamura, R.N., Graffeo, K.A., Thieme, M.E., 1997.
Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am. J. Psychiatry 154 (4), 457–465. Tran, P.V., Hamilton, S.H., Kuntz, A.J., Potvin, J.H., Andersen, S.W., Beasley Jr., C., Tollefson, G.D., 1997. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J. Clin. Psychopharmacol. 17 (5), 407–418.
Characteristics of two alternative schizophrenia remission definitions: Relationship to clinical and quality of life outcomes Eduardo Dunayevich ⁎, Gopalan Sethuraman, Mark Enerson, Cindy C. Taylor, Daniel Lin Lilly Research Laboratories, Indianapolis, IN, 46285, USA Received 9 November 2005; received in revised form 31 May 2006; accepted 5 June 2006 Available online 24 July 2006
Abstract Background: The goal of these secondary analyses of clinical trial data was to characterize clinical outcomes in patients with schizophrenia who met symptom severity or duration thresholds for two alternative definitions of remission, and to explore their relationships to improvement duration and quality of life outcomes. Methods: Definition 1 used threshold criteria for selected PANSS items sustained over at least 6-months Definition 2 used Brief Psychiatric Rating Scale (BPRS) % change, a threshold score for the Clinical Global Improvement-Severity (CGI-S) maintained for at least 8 weeks, and threshold scores for selected BPRS items. Positive and Negative Symptom Scale (PANSS) and Quality of Life scale (QLS) total scores were pooled from 6 clinical trials. The extent to which the alternative severity thresholds from these two definitions and duration of clinical improvement were associated with different clinical and QLS outcomes was explored. Regression analysis also assessed the relative contribution of each of the components of the two definition severity thresholds to improvements in QLS Total score. Results: Increases in QLS scores were greater for those patients who met either threshold criteria relative to those who met neither (p < .0001). Significantly greater improvements in QLS scores were observed for patients who met either threshold criteria at the 8-, 16- and 24-week visits relative to those who met criteria at weeks 16 and 24, or at week 24 only (p < 0.001), as well as for the subset of patients who met threshold criteria at both 24 and 52 weeks relative to those who met criteria at only one of these 2 time points. Only 31% to 47% of patients meeting threshold criteria for either definition at the 8-, 16- or 24-week visits remained in remission at the 52-week visit. Among the severity threshold components analyzed, BPRS total % change from baseline was the strongest predictor of improvement in QLS scores. Conclusions: Quality of life improved most for patients who achieved severity thresholds associated with either remission criteria and who stayed improved for longer periods. Total BPRS change scores accounted for the greatest percentage of the QLS scores variance. Only a fraction of patients who meet severity criteria for either remission definition early in treatment will remain at that level of improvement within the subsequent 9–12 months. © 2006 Elsevier B.V. All rights reserved. Keywords: Schizophrenia; Meta-analysis; Remission; Quality of life; Antipsychotics; Functional outcomes
1. Introduction ⁎ Corresponding author. Tel.: +1 317 651 2602; fax: +1 317 277 6896. E-mail address: [email protected] (E. Dunayevich). 0920-9964/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2006.06.002
There has been a recent initiative to establish consensus on criteria defining remission in schizophrenia (Andreasen et al., 2005). A broadly accepted
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remission definition would assist in establishing standards for adequate care, facilitating meaningful comparisons between therapeutic agents, and for use in the development of novel therapeutics. Current conceptualizations of remission are based on the assumption that in schizophrenia, as in other psychiatric disorders such as depression and anxiety, a clinical severity threshold can be defined that reflects a relative absence of the hallmark symptoms of the disorder. In a recent analysis of a clinical trial comparing olanzapine with risperidone in patients with schizophrenia, differences in outcomes between treatment groups with respect to duration of time in remission were observed when elements of two proposed definitions of remission were applied (Breier et al., 2003; Sethuraman et al., 2005). These findings underscore the potential utility of remission definitions and how they may relate to outcomes in schizophrenia. Thus far, proposed criteria for remission have focused predominantly on establishing clinical severity thresholds using some of the assessment tools currently available for the evaluation of symptoms, such as the Positive and Negative Symptom Scale (PANSS) or the Brief Psychiatric Rating Scale (BPRS). Minimal duration of maintaining clinical severity threshold requirements have also been proposed. However, empirical evidence supporting clinical and duration requirements has been limited to date (Lieberman et al., 2003; Andreasen et al., 2005). Additionally, Quality of Life (QOL) measures, while not usually included in the proposed definitions of remission, have also become important indicators of outcome: Double-blind clinical studies have demonstrated QOL improvement during antipsychotic treatment (Hamilton et al., 1998, 2000; Marder et al., 2003; Revicki et al., 1999). Significant correlations have been demonstrated between QOL and the severity of symptoms in schizophrenia (BowThomas et al., 1999; Breier et al., 1991; Mueser et al., 1991); and schizophrenia patients who attain symptomatic remission over the course of antipsychotic treatment are likely to experience greater improvements in QOL than those who do not. The goal of the secondary analyses of pooled clinical trial data presented in this manuscript was to explore the characteristics of patients who met clinical severity or duration thresholds for two alternative definitions of remission (Andreasen et al., 2005; Lieberman et al., 2003) and the relationship of these thresholds to QOL outcomes. These definitions were especially useful for the purposes of comparison as they were dissimilar in several ways: One was intended for recent-onset or acute schizophrenia, used clinical rating change total scores as one of its main components, and established a
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minimum duration criterion of 8 weeks (Lieberman et al., 2003), while the other was intended for chronic schizophrenia, used absolute severity thresholds, and a minimum duration requirement of 6 months (Andreasen et al., 2005). More specifically, we aimed to examine, 1. If patients achieving either of these alternative severity thresholds differed meaningfully from those patients who did not reach them in clinical and QOL ratings; 2. Whether meeting alternative severity thresholds is associated with different degrees of clinical and QOL improvement. 3. Which elements of these alternative severity thresholds accounted for the greatest degree of variance in QOL outcomes; 4. If a longer time displaying improvement consistent with either threshold was associated with varying degrees of QOL improvement; 5. The effects of applying increasingly greater duration requirements on the predictive value of these clinical severity thresholds. 2. Methods 2.1. Patient population and study design The present post hoc analyses used pooled data derived from 6 double-blind, randomized, multicenter clinical trials, comparing olanzapine with other antipsychotic drugs: vs. risperidone (N = 339, Tran et al., 1997, vs. ziprasidone (N = 944, Breier et al., 2005; N = 394, Kinon et al., 2006), vs. quetiapine (N = 347, Kinon et al., 2003), vs. haloperidol (N = 1996, Tollefson et al., 1997), and vs. haloperidol and risperidone (N = 414, Breier et al., 2003). Complete details and primary results of these clinical trials are reported elsewhere. Briefly, the subjects were inpatients or outpatients, either sex, aged 18–75 years with a diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder (DSM-IV). To be included in the present analyses, patients had to have a baseline value and one subsequent QOL assessment. The Breier et al. (2003) study enrolled a population of relatively stable schizophrenic patients, the Kinon et al. (2003) study enrolled patients with predominant negative symptoms, and the Kinon et al. (2006) study enrolled patients with prominent depressive symptoms; the other 3 studies enrolled patients who were experiencing an acute exacerbation of psychotic symptoms. Four studies were 6 months in duration of blinded therapy, two (Tollefson et al., 1997; Breier et al., 2003) were longer (24 and 12 months, respectively). Observations from the subset of patients who participated in these 2 longer studies for up to 12 months were pooled for exploratory analyses on the effects of time on QLS scores, and to
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assess proportion of patients meeting threshold criteria at the week 8, 16 or 24 timepoints who continued to meet criteria at the 52 week timepoint. 2.2. Definitions of clinical severity threshold criteria Clinical severity thresholds from 2 alternative definitions of remission were used for the present analyses. Definition 1 was developed by an expert consensus panel and required that a patient achieve scores of no greater than 3 (mild) concurrently on each of the following PANSS items: delusions, conceptual disorganization, hallucinatory behavior, blunted affect, passive/apathetic social withdrawal, lack of spontaneity and conversation flow, mannerisms and posturing, and unusual thought content (Andreasen et al., 2005). The panel also suggested that a patient maintain this level of symptom severity for a minimum of 6 months. Definition 2, which was proposed by Lieberman et al. (2003), required that a patient achieve 50% reduction in BPRS Total score from baseline, scores of ≤3 concurrently on each of the BPRS psychosis items (unusual thought content, suspiciousness, hallucinations, conceptual disorganization, mannerisms and posturing), and Clinical Global Impressions-Severity (CGI-S) score ≤ 3 for a minimum of 8 weeks. (Note: CGI-S scores were not collected in two of the six studies used in this pooled analysis (Kinon et al., 2006). A criteria of CGI-I ≤ 2 (much improved to very much improved) was used in place of CGI-S in those cases, except in regression analyses were only CGI-S data was used). 2.3. Statistical methods At each timepoint (8, 16, and 24 weeks), patients were grouped according to whether they met clinical severity threshold for 1.) Definition 1 criteria, but not Definition 2 criteria (Definition 1 exclusive); 2.) Definition 1 criteria including those who also met Definition 2 criteria (Definition 1 inclusive); 3.) Definition 2 criteria including those who also met Definition 1 criteria (Definition 2 inclusive); 4.) Definition 2 criteria excluding those who also met Definition 1 criteria (Definition 2 exclusive); 5) Either Definition 1 or Definition 2 severity criteria (Either); or 6.) Neither criteria (Neither). Overall group assignments were determined based on whether a patient met either severity threshold criteria at any time point (neither vs. either); for those that met severity threshold criteria, it was determined by which threshold(s) they met at any time in the study. The baseline and demographic characteristics were compared between groups using ANOVA with contrasts
of pair-wise comparisons for the continuous variables (age, age of onset, duration of illness, baseline PANSS total score, baseline QLS total score, number of prior hospitalizations, length of stay in hospital), or Fisher's exact test for categorical variables (gender, ethnicity [Caucasian vs. all others]). An ANCOVA model was used to analyze mean PANSS Total score changes from baseline at the 8-, 16-, and 24-week endpoints. The model included the severity group as the sole independent variable, with baseline PANSS as a continuous covariable. Severity groups were compared against the Neither group with contrasts using the Student–Newman–Keuls method from the ANCOVA model (Other comparisons between severity groups could not be performed due to overlaps in group membership). To facilitate comparisons across all groups, estimates of effect size on PANSS total score were also calculated relative to the Neither group. Due to change in group membership from timepoint to timepoint, the change scores were calculated separately for each of the 8-, 16-, and 24-week endpoints. Similar analyses of mean QLS Total score changes from baseline at 8-, 16-, and 24-week and 52 week endpoints were performed according to the above severity groupings, using an ANCOVA model to compare the dependent variable of QLS change scores. The model included the severity group as an independent class variable along with the baseline QLS score as a continuous covariable. Severity threshold groups were compared against the Neither group with contrasts using the Student–Newman–Keuls method from the ANCOVA model (Other comparisons could not be performed due to the overlaps in group membership). To facilitate comparisons across all groups, estimates of effect size on QLS change scores were also calculated for the severity groups relative to the Neither group. Due to change in group membership from timepoint to timepoint, the change scores were calculated separately for each of the 8-, 16-, and 24-week endpoints. To assess the contribution of the different elements constituting the severity thresholds for Definition 1 and Definition 2 to QLS change scores, BPRS total % change from baseline, CGI-S scores (from the 4 studies where CGI S data was available) and the combined 8 items of the PANSS that were included in the Definition 1 severity threshold were analyzed using stepwise regression analysis. To assess the impact of time meeting severity criteria on QOL measures, the following analyses were performed: 1) A comparison of mean QLS total score change from baseline to week 8, week 16 and week 24 for patients using a repeated measures mixed model
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ANCOVA to compare the dependent variable of QLS change scores. The model included the clinical severity groups “Either” or “Neither” as the independent class variable along, baseline QLS score as a continuous covariable, and patients as a random effect. The covariance structure of the R matrix in the model was set to the default structure of variance components. The analyses were performed separately for the groups that met or did not meet severity threshold (i) at week 8, week 16 and week 24, (ii) week 16 and week 24 but not week 8, (iii) week 24 but not week 8 and 16. To assess time effects on QLS beyond 24 weeks across severity threshold groups, the data from patients in the Tollefson et al. (1997) and Breier et al. (2003) studies who completed at least 12 months of study participation was fitted to an ANCOVA model to compare the mean QLS Total score change from baseline to week 24 and week 52 between the “either” and “neither” improvement groups. The model included the clinical severity groups “Either” or “Neither” as the independent class variable and baseline QLS score as a continuous covariable. Lastly, to further explore what timepoints after initiating therapy may be most indicative of a sustained clinical response (in this case, defined as maintaining Definition 1 or Definition 2 severity threshold at the 52 week timepoint), we calculated the proportion of patients from the Tollefson et al. (1997) and Breier et al. (2003) studies who met severity thresholds at the week 8, 16 and 24 timepoints and continued to meet severity threshold criteria at the week 52 timepoint.
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All statistical analyses was done using the SAS© version 8.2 (Cary, NC). 3. Results Out of 3626 randomized patients, 2771 (76%) had baseline values and at least 1 subsequent QOL assessment. Of the 2771 patients included in the present analyses, 50.1% (N = 1389) completed 6 months of blinded study therapy. Over the 6-month period where all 6 studies contributed data, discontinuation due to adverse events occurred in 11.1% of patients, 10.4% discontinued due to lack of efficacy as perceived by the patient, physician or both, with the remainder of discontinuations (28.6%) due to “other” reasons. “Other” reasons included patient conflict or decision, lost to follow-up, protocol violation, physician decision, noncompliance, protocol entry criteria not met, protocol variance, sponsor decision, moved away, protocol interim criteria not met, and satisfactory response. The proportion of patients who met either improvement threshold criteria at any time during the 6-month analysis period was 65.9% (N = 1825). All but 70 patients meeting Definition 2 clinical severity criteria also met Definition 1 criteria. As such, Definition 1 inclusive became essentially synonymous with “all patients who met criteria for either definition”. Due to the small sample size relative to the Either group (< 5%), no further separate analyses were performed for the Definition 2 exclusive group. Baseline characteristics for patients included in the present analyses are shown
Table 1 Baseline patient characteristics by severity group a Characteristic
Neither (N = 608)
Either b (N = 1825)
Definition 1 exclusive (N = 902)
Definition 2 inclusive c (N = 923)
Neither + Either (N = 2433)
No baseline and/ or post-baseline QLS (N = 920)
Age, years Male, N (%) Caucasian, N (%) Age of onset, years PANSS total score PANSS positive score PANSS negative score QLS total score No. of hospitalizations Hospital. duration, days Illness duration, years
39.7 ± 11.1 438 (72.0) 382 (62.8) 23.1 ± 7.9 93.9 ± 18.7 22.0 ± 6.0 25.7 ± 6.4 46.0 ± 19.8 1.1 ± 1.0 18.8 ± 42.1 16.5 ± 10.2
39.1 ± 10.5 1182 (64.8) ⁎ 1118 (61.3) 23.6 ± 7.9 86.1 ± 18.2 ⁎ 20.4 ± 5.7 ⁎ 22.7 ± 6.2 ⁎ 56.2 ± 20.8 ⁎ 0.8 ± 0.9 ⁎ 17.3 ± 43.1 15.5 ± 10.1 ⁎
40.3 ± 9.9 593 (65.7) ⁎ 521 (57.8) 23.5 ± 7.6 82.9 ± 17.0 ⁎ 19.4 ± 5.5 ⁎ 21.8 ± 6.0 ⁎ 57.1 ± 20.1 ⁎ 0.7 ± 1.0 ⁎ 25.3 ± 63.8 16.8 ± 9.7
38.0 ± 11.0 ⁎ 589 (63.8) ⁎ 597 (64.7) 23.8 ± 7.9 89.2 ± 18.8 ⁎ 21.5 ± 5.7 ⁎ 23.5 ± 6.3 ⁎ 55.4 ± 21.4 ⁎ 0.9 ± 0.9 ⁎ 13.4 ± 27.4 14.2 ± 10.0 ⁎
39.3 + 10.7 1620 (66.6) 1500 (61.7) 23.5 + 7.9 88.0 + 18.4 20.8 + 5.8 23.4 + 6.3
38.6 + 11.1 ⁎⁎ 586 (63.7) 674 (73.3) 23.8 + 7.7 92.8 + 19.7 ⁎⁎ 22.03 + 6.2 ⁎⁎ 24.6 + 6.9 ⁎⁎
0.9 + 0.9 17.7 + 42.7 15.7 + 10.1
1.4 + 1.0 ⁎⁎ 41.2 ± 64.3 ⁎⁎ 14.8 + 10.5 ⁎⁎
a
Reported as mean ± S.D. unless otherwise indicated. Baseline characteristics for the Definition 1 inclusive group were similar to the "Either" group; only 70 patients from the Definition 2 group were not part of the Definition 1 inclusive group. c Includes patients who also met Definition 1 criteria. ⁎ p < 0.05 vs Neither. ⁎⁎ p < 0.05 vs. Neither + Either. b
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in Table 1. There were 2410 total patients randomized in the two studies combined. Of these 1421 (59%) patients had one post-baseline QLS measurement. 502 patients (21%) completed 52 weeks of the study and had a QLS measurement at week 52. On the basis of the severity threshold criteria groupings, mean baseline PANSS Total, and Positive and Negative symptom subscale scores were significantly higher in patients in the Neither group relative to those in the Either group. The Neither group also had a significantly lower (10 points) mean baseline QLS Total score relative to the Either group, consisted of a higher proportion of males, a longer duration of illness, and a greater number of previous hospitalizations. The absolute number of patients meeting either of these severity threshold criteria decreased over time, however the proportion of patients meeting these thresholds increased due to greater patient attrition in the “Neither” group. (Fig. 1). Decreases in mean PANSS Total, Positive and Negative scores from baseline were significantly greater at all time points for all groups relative to the Neither group (p < 0.0001) (Fig. 2). The mean reductions in PANSS Total score (and corresponding effect sizes) at week 24 were − 21.7 (E.S. 0.4) for Definition 1
Fig. 1. Visit-wise proportion of patients meeting severity threshold criteria.
Fig. 2. Visit-wise PANSS Total scores for the different severity groups.
exclusive, − 33.9 (E.S. 1.0) for Definition 1 inclusive, and − 42.6 (E.S. 1.6) for Definition 2 inclusive groups. Mean changes from baseline in QLS Total score across visits (Fig. 3) were significantly greater at all time points for all groups relative to the Neither group (all p < 0.0001). At week 24, mean changes in QLS Total score from baseline, and associated effect sizes relative to the Neither group, were 8.9 ± 17.8 (n = 323) (E.S. 0.31) for Definition 1 exclusive, 15.4 ± 20.6 (n = 719) (E. S. 0.63) for Definition 1 inclusive, and 19.6 ± 20.9 (n = 456) (E.S. 0.87) for Definition 2 inclusive. The change from baseline for the Neither groups was 3.8 ± 15.8 (n = 610). The results of the stepwise regression analysis indicate that the BPRS total % change from baseline accounted for 15–22% of the variance between weeks 8–24, CGI-S scores (from the 4 studies where CGI S data was available) accounted for 2–3%. The aggregate of the 8 items of the PANSS included in Definition 1 severity threshold did not account for significant QLS variance at any time between weeks 8–24. Patients who reached severity threshold criteria for either Definition 1 or Definition 2 earliest and then sustained improvement meeting (and thus spent the longest time meeting criteria for either threshold) experienced significantly greater improvements in
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Table 2b Mean change from baseline in QLS total scores for patients meeting severity threshold criteria at both weeks 24 and 52 by severity group
Fig. 3. Visit-wise QLS total score mean change by severity group.
QLS Total score at week 24 relative to those who reached the threshold at either week 16 or only at week 24 (QLS change scores of 17.6 for those who met threshold at 8, 16 and 24 weeks (N = 514), vs. 12.6 for those meeting threshold at only 16 and 24 weeks (N = 114), and 6.4 for those meeting either threshold at 24 weeks only (N = 73), p <0.001). Among patients who met either threshold at all visits, QLS Total scores increased significantly across visits (12.0, 16.0, and 17.6 at 8, 16 and 24 weeks, respectively, p < 0.001). In the 12-month completer subset, similar findings of greater gains in QLS scores for patients who met the severity threshold for either definition longest, in this case at both weeks 24 and 52, were noted compared to patients who only reached severity threshold for either definition only at week 24 or only at week 52 (Table 2a). The QLS scores between patients who met threshold Table 2a Mean change from baseline in QLS total scores based on meeting severity threshold criteria Met threshold at week 24
Met threshold at week 52
Mean change from baseline in QLS Total Score
Yes No Yes
Yes Yes No
Week 24 9.6 9.1 5.2
Week 52 14.9 6.9 11.9
Severity group
QLS total scores, week 24
QLS total scores, week 52
Definition 1 inclusive (N = 160) Definition 2 inclusive (N = 113) Neither (N = 149)
10.4
16.1
12.5
18.8
3.8
3.9
criteria for Definition 1 inclusive or Definition 2 inclusive at both week 24 and week 52 timepoints appeared comparable (Table 2b). In the 12-month subset, the proportion of patients who met threshold criteria for either Definition 1 inclusive or Definition 2 inclusive at week 52 relative to all the patients meeting these criteria at earlier timepoints increased over time: 137/433 (31%), 139/358 (38%) and 160/334 (47%) of Definition 1 inclusive patients, as well as 96/297 (32%), 97/250 (38%) and 113/238 (47%) of Definition 2 patients at weeks 8, 16 and 24, respectively, were still meeting threshold criteria at week 52. 4. Discussion In these secondary analyses of pooled data from 6 clinical trials, comparisons between two clinical severity thresholds used in alternative definitions of remission indicated that the severity threshold for Definition 2, proposed by Lieberman et al. (2003), appeared more stringent than the threshold set for definition 1 (Andreasen et al., 2005), as almost all patients achieving the Definition 2 threshold also achieved the Definition 1 threshold, while the converse was not apparent. The smaller number of patients achieving the Definition 2 severity threshold experienced numerically greater mean improvements in PANSS and QLS total scores than those achieving the Definition 1 severity threshold. While no statistical testing could be performed between these groups due to overlapping membership, the greater effect sizes calculated on PANSS and QLS total change scores for the Definition 2 inclusive compared to Definition 1 inclusive, with the smallest effect sizes for the Definition 1 exclusive lend further support to this observation. As QLS total scores were sensitive to degree of improvement achieved by the different severity groups, we assessed the magnitude of the effect of constituting elements of these definitions' severity threshold on QLS scores by means of a regression analysis. In this dataset
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of mostly acutely ill patients, BPRS change scores accounted for the greatest effect on QLS total scores variance. This finding appeared consistent with the higher level of stringency of the Definition 2 severity threshold manifested in this sample. To what extent these differences in remission severity threshold may be clinically meaningful becomes more apparent when the effects of time are factored in. Only about 1/3 (8 weeks after initiating study therapy) to less than 1/2 of the patients meeting either of these severity thresholds (24 weeks after study initiation) maintained this level of improvement at the one-year time point. It appears that meeting either of these severity thresholds by themselves holds limited utility in predicting the patients who will sustain improvement at later timepoints. In these analyses, longer duration of sustained improvement identified an increasingly larger fraction of patients who would be in remission at the 52-week timepoint. While specific cutoffs were not explored, our findings suggest that a relatively stringent duration criteria may be a useful element of a remission definition. Improvements over time in Quality of Life scores were the greatest for the group of patients who met the severity threshold for greater than 6 months. While this finding is also supportive of stringent time requirements in a remission definition such as the one proposed by Andreasen et al. (2005), it is confounded by speed of improvement onset: The patients who achieved either severity threshold at the 8-week timepoint and then sustained it for the following 16 weeks were the ones who experienced the greatest gains in QLS scores. Indeed, most (160/237, 77%) of the patients who remained in remission by either criteria at week 52 had already crossed the severity threshold at week 8. In other words, while reaching clinical severity threshold for remission rapidly is no guarantee of remaining in remission, those who improve slowly are less likely to achieve sustained remission, at least if no changes in clinical management are instituted. A more encouraging finding is the observation that, for those patients who maintain clinical improvement (as indicated by sustained achievement of severity threshold criteria) QLS scores continue to improve up to the 52 week timepoint. While this may be a small subset of this large pooled dataset, the findings indicate that, at least for some patients, gradual improvement of function in the setting of sustained clinical improvement beyond the acute treatment period may be possible. The interpretation of these findings needs to be tempered by several limitations of these analyses. First, more than 50% of the initial randomized sample had discontinued study participation at the 6 month endpoint, and the patients with data beyond 6 months of
study participation were only a fraction of the entire dataset. While high levels of study discontinuation are common in schizophrenia clinical trials, the high degree of attrition reported here may have biased the findings reported here, especially because our analyses were on the subset of patients who provided at least one QLS measure after the baseline assessment. It is noteworthy that a greater proportion of patients discontinuing the study between weeks 8 and 24 were from the Neither group, consistent with reports indicating that lack of efficacy is an important driver of study discontinuation (Liu-Seifert et al., 2005). Thus it is possible that the subset that provided post-baseline measures may have experienced overall better outcomes than the patients who did not. Second, the limited period encompassed by our analyses does not allow to adequately disentangle the effects of duration of remission from speed of improvement on QLS. In other words, the effects of longer time meeting improvement criteria on QLS scores could be due to the cumulative beneficial effects of sustained improvement on QLS or that the longer time meeting threshold criteria mainly identifies patients with faster treatment response and better outcomes who consequently remained in an improved state for a longer proportion of the observation periods considered here. Additionally, as these analyses encompassed only a 6- to 12-month period, they may have inappropriately allocated to the Neither group patients who may have experienced sufficient improvement to meet threshold criteria at a later time point. Such patients, however, are likely to be few. It should also be noted that there were significant differences in baseline PANSS and QLS Total scores between non-improvers and improvers, consistent with the notion that greater illness severity and chronicity is associated with lower likelihood of achieving remission (Lasser et al., 2005). Lastly, different results may have been obtained if these analyses had been run in a sample of primarily subacute or chronic patients. Under those circumstances, it is entirely possible that only limited change may have been observed over time for PANSS and QLS scores, or that the severity threshold for Definition 1 may have been more stringent than for Definition 2. While this large dataset of pooled clinical trial patients encompasses patients with a range of baseline characteristics (including patients with symptoms of acute exacerbation as well as more stable and also patients with predominantly depressed symptoms) that suggests the findings could be generalized to other schizophrenia populations, pooling of data may also create additional confounders. Thus, caution in the interpretation of the findings reported here is warranted.
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Overall, our findings support the notion that a relatively extended longitudinal component should be integral to remission criteria. Only a minority of patients who meet remission severity thresholds early in the course of treatment sustain the clinical improvement at later timepoints. Moreover, quality of life scores improved progressively with increasing time remaining improved, regardless of threshold used, and the greatest QOL improvements were observed in patients with the earliest and longest time remaining improved. These findings are consistent with the view that, for some patients who experience sustained clinical improvement, the benefits of antipsychotic treatment on functional outcomes may accrue beyond the initial, acute treatment period (Dunayevich et al., 2005). Our findings provide only limited support to the notion that differences in the severity thresholds of Definition 1 and Definition 2 are clinically meaningful. The greater support found in our results for a relatively stringent duration threshold may simply reflect that longer time remaining in therapy, as suggested by the CATIE study results (Lieberman et al. 2005) may be one of the most important prognostic factors in the treatment of schizophrenia. In summary, the present findings examine the impact of different clinical severity and duration of improvement thresholds on the number of patients participating in clinical trials who achieve these thresholds, and the degree of clinical and QLS improvement they evidenced. Since a goal of establishing improvement and remission criteria is to define outcomes that are predictive of eventual functional recovery, definitions that encompass a concurrent and sustained resolution of symptoms as well as greater improvements in quality of life may have greater validity and practical utility. Elements from each of the remission criteria considered here, such as change scores and duration requirements, may be useful to characterize treatment outcomes, and further refinements to the composition of remission definitions may improve their utility. As proposed by Andreasen et al. (2005) additional prospective analyses in long-term studies to further examine alternative remission criteria and their relevance to quality of life and functional outcomes are needed. References Andreasen, N.C., Carpenter Jr., W.T., Kane, J.M., Lasser, R.A., Marder, S.R., Weinberger, D.R., 2005. Remission in schizophrenia: proposed criteria and rationale for consensus. Am. J. Psychiatry 162 (3), 441–449. Bow-Thomas, C.C., Velligan, D.I., Miller, A.L., Olsen, J., 1999. Predicting quality of life from symptomatology in schizophrenia at exacerbation and stabilization. Psychiatry Res. 86 (2), 131–142.
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