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Relationship between the clinical global impression of severity for schizoaffective disorder scale and established mood scales for mania and depression
Journal of Affective Disorders 150 (2013) 17–22
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Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Review
Relationship between the clinical global impression of severity for schizoaffective disorder scale and established mood scales for mania and depression$ Ibrahim Turkoz a,n, Dong-Jing Fu b, Cynthia A. Bossie b, John J. Sheehan b,c, Larry Alphs b a
Janssen Research & Development, LLC, 1125 Trenton-Harbourton Road, Titusville, NJ 08650, USA Janssen Scientific Affairs, LLC, Titusville, NJ, USA c Bristol-Myers Squibb, Plainsboro, NJ, USA b
a r t i c l e i n f o
abstract
Article history: Received 21 December 2012 Accepted 30 January 2013 Available online 18 March 2013
Background: This analysis explored the relationship between ratings on HAM-D-17 or YMRS and those on the depressive or manic subscale of CGI-S for schizoaffective disorder (CGI-S-SCA). Methods: This post hoc analysis used the database (N ¼ 614) from two 6-week, randomized, placebocontrolled studies of paliperidone ER versus placebo in symptomatic subjects with schizoaffective disorder assessed using HAM-D-17, YMRS, and CGI-S-SCA scales. Parametric and nonparametric regression models explored the relationships between ratings on YMRS and HAM-D-17 and on depressive and manic domains of the CGI-S-SCA from baseline to the 6-week end point. A clinically meaningful improvement was defined as a change of 1 point in the CGI-S-SCA score. No adjustment was made for multiplicity. Results: Multiple linear regression models suggested that a 1-point change in the depressive domain of CGI-S-SCA corresponded to an average 3.6-point (SE ¼0.2) change in HAM-D-17 score. Similarly, a 1-point change in the manic domain of CGI-S-SCA corresponded to an average 5.8-point (SE ¼ 0.2) change in YMRS score. Results were confirmed using local and cumulative logistic regression models in addition to equipercentile linking. Limitations: Lack of subjects scoring over the complete range of possible scores may limit broad application of the analyses. Conclusion: Clinically meaningful score changes in depressive and manic domains of CGI-S-SCA corresponded to approximately 4- and 6-point score changes on HAM-D-17 and YMRS, respectively, in symptomatic subjects with schizoaffective disorder. & 2013 Elsevier B.V. All rights reserved.
Keywords: Schizoaffective disorder Clinical global impression-severityschizoaffective disorder Hamilton rating scale-depression, 17-Item version Young mania rating scale
Contents 1. 2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 2.1. Study design. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 2.2. Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 3.1. Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 3.2. Clinically meaningful changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 3.2.1. CGI-S-SCA depressive domain and HAM-D-17 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 3.2.2. CGI-SCA mania domain and YMRS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 3.3. Sensitivity analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
$ Prior presentation: Parts of these data were previously presented as a poster at the 7th Annual International Society for CNS Clinical Trials and Methodology Scientific Meeting, February 21–23, 2011, Washington, DC, and the 51st Annual New Clinical Drug Evaluation Unit Meeting, June 13–16, 2011, Boca Raton, FL, USA. n Corresponding author. Tel.: þ609 730 7719; fax: þ 609 730 3125. E-mail address: [email protected] (I. Turkoz).
0165-0327/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2013.01.047
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4.
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 4.1. Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
1. Introduction Schizoaffective disorder identifies a clinical entity whose symptoms encompass criteria for schizophrenia, as well as for a major depressive, manic, or mixed episode (American Psychiatric Association, 2006). Studies of schizoaffective disorder have traditionally used a combination of scales designed to assess schizophrenia or mood disorders, such as the Positive and Negative Syndrome Scale (PANSS), the Young Mania Rating Scale (YMRS, Young et al., 1978), and the Hamilton Rating Scale-Depression, 17- and 21-item versions (HAM-D-17 and HAM-D-21) (Hamilton, 1967, Vieta et al., 2001). Although these scales are used to measure schizoaffective disorder in clinical trial settings, clinically meaningful changes in scale scores on these instruments are not well established. Data are often evaluated as change scores, as percent reductions, or in relation to a predefined threshold score. YMRS scores of approximately 13, 20, 26, and 38 have been suggested to correspond to minimal, mild, moderate, and severe manic symptom severity levels, respectively (Young et al., 1978). In a comparison of acute and longer-term treatment outcomes of the Sequenced Treatment Alternatives to Relieve Depression trial, HAM-D-17 scores of 0 to 7, 8 to 13, 14 to 19, 20 to 25, and 26 and higher corresponded to no, mild, moderate, severe, and very severe depressive symptoms, respectively (Rush et al., 2006). Although these data may facilitate approximation of what might be considered a meaningful change score, such interpretation is limited. For example, from the HAM-D data, a 1-point change could shift categories of severity but is unlikely to be considered a clinically relevant change. A meta-analysis of seven trials of major depressive disorder suggests that a 4-point or less reduction in HAM-D-17 score indicated no improvement in symptomatic subjects (Furukawa et al., 2007). Several other publications have examined relationships between various psychiatric scales with the intent of helping to define clinically meaningful changes. For example, a correlation was reported between Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression (CGI) ratings in symptomatic subjects with schizophrenia (Leucht et al., 2005a). A CGI-Improvement (CGI-I) rating of ‘‘minimal improvement’’ was associated with BPRS reductions between 1 and 4 weeks of treatment of 24% to 30%, whereas a rating of ‘‘much improved’’ corresponded to BPRS reductions of 44% to 58% (Leucht et al., 2005a). In another study of subjects with schizophrenia, Leucht et al. reported that a reduction in PANSS of approximately 50% corresponded to a ‘‘much improved’’ CGI-I rating (Leucht et al., 2005b). Furthermore, an equipercentile linking analysis of PANSS, BPRS, and CGI ratings from 14 drug trials in acutely ill subjects with schizophrenia reported that an absolute reduction in BPRS/PANSS by 10–15 points corresponded to a CGI-I of ‘‘minimally improved’’ and to a change in the CGI-S score of 1 point (Leucht et al., 2006). However, such a change is highly dependent on initial scores at baseline. Published reports describing clinically meaningful changes in CGI-S with the commonly used mood scales, YMRS and HAM-D, are limited and have not discussed the schizoaffective population (Kemp et al., 2011; Furukawa et al., 2007).
The Clinical Global Impression-Severity (CGI-S) scale has been widely used to measure clinical outcomes in symptom severity and treatment efficacy in subjects with psychoses (Guy, 1976). This scale has ratings from 1 (not ill) to 7 (extremely ill) (Guy, 1976), and, empirically, a change of 1 or more points on the CGI-S can be considered clinically meaningful. Change on this scale has strong face validity, and the usefulness of this measurement approach is reflected in the fact that many disorder-specific CGI scales have been introduced into clinical trials, among them the CGI for schizophrenia (CGI-SCH) (Haro et al., 2003), for bipolar disorder (CGI-BP) (Spearing et al., 1997), and, more recently, for schizoaffective disorder (CGI-S-SCA). The latter includes ratings of severity of the four schizoaffective disorder domains (positive, negative, manic, and depressive), plus an overall rating (Allen et al., 2012). This analysis explored the relationships between ratings on both the HAM-D-17 and the YMRS and those on the depressive and manic domains of the CGI-S-SCA, to determine which change score on the mood scales corresponds to a 1-point (i.e., clinically meaningful) change on the CGI-S-SCA in subjects with schizoaffective disorder (Canuso et al., 2010a, 2010b, 2010c).
2. Methods 2.1. Study design This post hoc analysis used a database (N ¼614) composed of two six-week, randomized, placebo-controlled studies of paliperidone ER treatment versus placebo in subjects with schizoaffective disorder (Canuso et al., 2010a, 2010b, 2010c), which included similar subject populations and study designs (NCT00412373, NCT00397033). All subjects had been given a confirmed diagnosis of schizoaffective disorder based on the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV-TR), Disorders (SCID). Subjects had an acute exacerbation of schizoaffective disorder, with YMRS and/or HAM-D-21 scores Z16 and PANSS total scores Z60 (plus scores Z4 on Z2 PANSS items [hostility, excitement, tension, uncooperativeness, and poor impulse control]). Subjects were permitted to receive concomitant treatment with mood stabilizers and/or antidepressants, provided these medications had been given at a stable dose within 30 days of screening. Assessments for the original studies included the HAM-D-21, YMRS, PANSS total, and CGI-S-SCA (overall score and manic and depressive domains). These were assessed at baseline, day 4, and weeks 1, 2, 3, 4, and 6 (end point). Ratings on these scales were based on symptoms during the week before the assessment visit. To focus on the core symptoms of depression, only the first 17 (HAM-D-17) of the 21 items of the HAM-D-21 scale were used in this post hoc analysis. All raters had clinical and/or research experience with this subject population, had participated in study-specific training, and had passed required certification for the scales. Whenever possible, the same raters at each site assessed the same subjects throughout the study.
I. Turkoz et al. / Journal of Affective Disorders 150 (2013) 17–22
2.2. Statistical analysis The intent-to-treat population used for this analysis included randomly assigned subjects who received at least one dose of study medication and at least one postbaseline efficacy evaluation. Clinically meaningful change was defined as a 1-point change in the CGI-S-SCA scale score. Simple and multiple (with explanatory study design variables for treatment, protocol, concomitant medication strata, and baseline score) regression models explored relationships between change scores on the HAM-D-17 and the YMRS and the depressive or the manic domain of the CGI-S-SCA scale, respectively, from baseline to the week 6 end point, as continuous dependent variables. Assumptions such as a linear relationship between variables and equal variances of error terms were evaluated using residual plots. Regression coefficients and r2 were calculated at each visit in addition to week 6 end point to support the consistency of observed estimates over time. Additional simple and multiple regression models were used to explore relationships between HAM-D-17 and YMRS and CGI-S-SCA depressive and manic domain scores from baseline to end point by concomitant medication status (with or without antidepressants and/or mood stabilizers). No adjustment was made for multiplicity. Ordinal logistic regression models were used to determine expected values of HAM-D-17 and YMRS at end point for each anchor point in the CGI-S-SCA. Additional logistic regression models were fitted using the change score of CGI-S-SCA as a categorical variable. Categories of change in CGI-S-SCA were defined as improved (severity score lowered one or more units), unchanged (0), or worsening (severity score increased by one or more units). Both YMRS and HAM-D-17 scores were also categorized. YMRS cut-off values were minimal (13), mild (20),
Simple regression Multiple regression
moderate (26), and severe (38) manic symptoms (Young et al., 1978), and HAM-D-17 cut-off scores were no (0 to 7), mild (8 to 13), moderate (14 to 19), severe (20 to 25), and very severe ( Z26) depressive symptoms (Rush et al., 2006). Predicted probabilities of CGI-S scores were computed for given YMRS and HAM-D cut-off points. Sensitivity analysis is an essential element in model building. Both equipercentile linking analysis and local regression approaches were employed. Equipercentile linking analysis (Price et al., 2001) was performed to determine the correspondence of CGI-S-SCA depressive domain scores to HAM-D-17 and HAM-D-21 scores, and of CGI-S-SCA manic domain scores to YMRS scores. Percentiles of the cumulative distribution of observed values for the two scales were mapped by the method of Leucht (Leucht et al., 2005b). Briefly, the equipercentile equating involved first determining percentile ranks for the relevant domain of CGI-S-SCA and HAM-D-17, HAM-D-21, or YMRS. Second, individual scores on the CGI-S-SCA scale and on the relevant mood scale with equipercentile rank were matched together. Equipercentile equating defines a nonlinear relationship between score scales by setting the percentile ranks equal for each point. Local regression models were conducted to allow greater flexibility than is seen with traditional modeling tools—an approach used in situations in which a suitable parametric form of the regression surface is not known. This approach is also appropriate when outliers are noted in the data and a robust fitting method is necessary.
3. Results 3.1. Subjects
Least squares estimates of HAM-D-17 point change (SE)
P value
r2
4.4 (0.2) 3.6 (0.2)
o 0.001 o 0.001
0.516 0.589
Least squares estimates of YMRS point change (SE)
P value
r2
Baseline demographic and clinical characteristics and improvement in efficacy measures from baseline to end point have been reported previously (Canuso et al., 2010a, 2010b, 2010c). Subjects’ mean age was 37 years, and 60% were male. The schizoaffective disorder type was bipolar in 69% of subjects and depressive in 31%. Nearly half of subjects (45%) were taking mood stabilizers and/or antidepressants. At baseline, subjects had a mean (standard deviation [SD]) YMRS score of 24.4 (10.0), a mean (SD) HAM-D-17 score of 16.8 (8.0), and mean (SD) CGI-S depression and manic domain scores of 3.2 (1.5) and 3.5 (1.5), respectively (Canuso et al., 2010c).
6.6 (0.2) 5.8 (0.2)
o 0.001 o 0.001
0.630 0.675
3.2. Clinically meaningful changes
Table 1 HAM-D-17 and YMRS changes associated with a 1-point change in CGI-S-SCA depressive and manic domains from baseline to endpoint.
Simple regression Multiple regression
19
Testing the hypothesis that the corresponding least squares estimates are equal to 0. P-valueo 0.05 indicates that there is strong evidence that the slope is not equal to 0. CGI-S-SCA: Clinical Global Impression-Schizoaffective Disorder, HAM-D-17: Hamilton Rating Scale-Depression, 17-item version, SE: standard error, YMRS: Young Mania Rating Scale.
3.2.1. CGI-S-SCA depressive domain and HAM-D-17 Results from simple and multiple regression models for CGI-SSCA depressive domain and HAM-D-17 are shown in Table 1. At the study end point, the simple regression model suggested that a 1-point change in score for the CGI-S-SCA depressive
Table 2 Distribution of HAM-D-17 scores by CGI-S-SCA depressive domain score at week 6 end point. Probabilities Z20% are highlighted in italic. Predictive probability of HAM-D-17 score at end point (%)
CGI-S-SCA depressive domain
0–7 n¼ 291
8–13 n ¼150
14–19 n ¼96
20–25 n ¼49
Z26 n ¼27
CGI-S-SCA ¼1 normal CGI-S-SCA ¼2 minimally ill CGI-S-SCA ¼3 mildly ill CGI-S-SCA ¼4 moderately ill CGI-S-SCA ¼5 markedly ill CGI-S-SCA ¼6/7 severely ill/extremely severely ill
62.9 23.7 11.3 1.4 0.7 0
19.3 26.7 44.7 8.0 1.3 0
5.2 12.5 41.7 36.5 4.2 0
0 0 14.3 59.2 20.4 6.1
0 0 0 25.9 51.9 22.2
Ordinal logistic regression model with HAM-D-17as a predictor (odds ratio: 1.36; 95% CI: 1.31 to 1.40). CGI-S-SCA: Clinical Global Impression-Severity-Schizoaffective Disorder, HAM-D-17: Hamilton Rating Scale-Depression, 17-item version.
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I. Turkoz et al. / Journal of Affective Disorders 150 (2013) 17–22
CGI-S-SCA mania domain corresponds to a least squares estimate of a 6.6-point (SE¼0.2) change in the YMRS. The multiple regression model identified this change to be 5.8 points (SE¼0.2) on the YMRS. The regression coefficient ranged between 5.0 and 6.6 units. The observed r2 ranged between 0.45 and 0.63, with numerically increasing values observed over time, and the highest value observed at week 6. These results suggest that the relationship between the two variables (CGI-S-SCA manic domain and YMRS) was consistent at each visit starting from week 1. The relationship between CGI-S-SCA and YMRS did not differ between subjects taking antidepressants and/or mood stabilizers and subjects receiving paliperidone ER monotherapy. Simple regression model-determined changes in scores for the CGI-S of manic symptoms from baseline to end point were 6.2 and 6.8, and r2 was 0.61 and 0.64, for subjects with and without concomitant medications, respectively. The logistic regression model-determined changes in the CGIS-SCA manic domain categories suggested an average 30% probability of a shift of one category at end point when the YMRS score changed by 1 point. Predictive probabilities of changes in the YMRS score for each CGI-S-SCA manic score are outlined in Table 3.
domain corresponded to an average least squares estimate of a 4.4-point (standard error [SE] ¼0.2) change in the HAM-D-17 score, whereas a multiple regression model suggested correspondence to an average least square estimate of a 3.6-point (SE ¼0.2) change in the HAM-D-17 score. The regression coefficient from least squares ranged between 3.9 and 4.4 units based on simple regression analysis. The observed r2 ranged from 0.45 to 0.52, with numerically increasing values observed over time, and the highest value observed at week 6. These results suggest that the relationship between the two variables (CGI-S-SCA depressive domain and HAM-D-17) was consistent at each visit. The overall relationship between CGI-S-SCA and HAM-D-17 did not differ between subjects taking antidepressants and/or mood stabilizers compared with those not taking concomitant medications. The simple regression analysis identified that changes in CGI-S depressive symptoms from baseline to end point for subjects with and without concomitant medications were 4.3 and 4.5, and r2 was 0.48 and 0.55, respectively. The logistic regression model with the CGI-S-SCA depressive domain categories of change suggested an average 36% probability of a shift of one category at end point when the HAM-D-17 score changed by 1 point. The predictive probability of the HAM-D-17 score range for each CGI-S-SCA depressive score is outlined in Table 2.
3.3. Sensitivity analysis 3.2.2. CGI-SCA mania domain and YMRS Results from simple and multiple regression models for the CGI-S-SCA mania domain and YMRS are shown in Table 1. A simple regression model suggests that a 1-point change in the
Figs. 1 and 2 show the equipercentile linking analyses and local regression models conducted between CGI-S-SCA depression and manic domain scores and HAM-D-17 and YMRS scores at each time point. For reference and sensitivity purposes, an
Table 3 Distribution of YMRS scores by CGI-S-SCA manic domain score at week 6 end point. Probabilities Z 20% are highlighted in italic. Predictive probability of YMRS score at end point (%)
CGI-S-SCA manic domain
0–7 n ¼202
8–12 n ¼113
13–19 n¼129
20–25 n¼ 74
26–37 n ¼71
Z 38 n¼ 24
CGI-S-SCA ¼1 normal CGI-S-SCA ¼2 minimally ill CGI-S-SCA ¼3 mildly ill CGI-S-SCA ¼4 moderately ill CGI-S-SCA ¼5 markedly ill CGI-S-SCA ¼6/7 severely ill/extremely severely ill
73.3 21.8 5.0 0 0 0
28.3 41.6 23.9 6.2 0 0
16.3 21.7 47.3 13.2 0.8 0.8
8.1 4.1 33.8 44.6 9.5 0
0 1.4 8.5 32.4 42.3 15.5
0 0 4.2 0 58.3 37.5
Extremely ill 7
Extremely ill 7
Severely ill 6
Severely ill 6
Markedly ill 5
Moderately ill 4 Baseline (N = 614) Day 4 (n = 609) Week 1 (n = 579) Week 2 (n = 508) Week 3 (n = 452) Week 4 (n = 429) Week 6 (n = 392)
Mildly ill 3
Minimally ill 2
Normal 1
CGI-S-SCA Depressive Domain Score
CGI-S-SCA Depressive Domain Score
Ordinal logistic regression model with YMRS as a predictor (odds ratio: 1.30; 95% CI: 1.26 to 1.33). CGI-S-SCA: Clinical Global Impression-Severity-Schizoaffective Disorder. YMRS: Young Mania Rating Scale.
Markedly ill 5
Moderately ill 4 Baseline (N = 614) Day 4 (n = 609) Week 1 (n = 579) Week 2 (n = 508) Week 3 (n = 452) Week 4 (n = 429) Week 6 (n = 392)
Mildly ill 3
Minimally ill 2
Normal 1 0
5
10
15
20
25
HAM-D-17 Total Score
30
35
40
0
5
10
15
20
25
30
35
40
HAM-D-17 Total Score
Fig. 1. Equipercentile linking (A) and local regression model (B) results between Clinical Global Impression-Severity-Schizoaffective Disorder (CGI-S-SCA) depression domain and Hamilton Rating Scale-Depression, 17-item version (HAM-D-17), scores at each time point.
Extremely ill 7
Extremely ill 7
Severely ill 6
Severely ill 6
Markedly ill 5
Moderately ill 4 Baseline (N = 614) Day 4 (n = 609) Week 1 (n = 579) Week 2 (n = 508) Week 3 (n = 452) Week 4 (n = 429) Week 6 (n = 392)
Mildly ill 3
Minimally ill 2
CGI-S-SCA Manic Domain Score
CGI-S-SCA Manic Domain Score
I. Turkoz et al. / Journal of Affective Disorders 150 (2013) 17–22
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Markedly ill 5
Moderately ill 4 Baseline (N = 614) Day 4 (n = 609) Week 1 (n = 579) Week 2 (n = 508) Week 3 (n = 452) Week 4 (n = 429) Week 6 (n = 392)
Mildly ill 3
Minimally ill 2
Normal 1
Normal 1 0
5
10
15
20
25
30
35
40
45
50
YMRS Total Score
0
5
10
15
20
25
30
35
40
45
50
YMRS Total Score
Fig. 2. Equipercentile linking (A) and local regression model (B) results between Clinical Global Impression-Severity-Schizoaffective Disorder (CGI-S-SCA) manic domain and Young Mania Rating Scale (YMRS) scores at each time point.
CGI-S-GCA Depressive Domain Score
Extremely ill 7
Severely ill 6
Markedly ill 5
Moderately ill 4 Baseline (N = 614) Day 4 (n = 609) Week 1 (n = 579) Week 2 (n = 508) Week 3 (n = 452) Week 4 (n = 429) Week 6 (n = 392)
Mildly ill 3
Minimally ill 2
Normal 1 0
5
10
15
20
25
30
35
40
45
HAM-D-21 Total Score
Fig. 3. Equipercentile linking results between Clinical Global Impression-SeveritySchizoaffective Disorder (CGI-S-SCA) depression domain and Hamilton Rating Scale-Depression, 21-item version (HAM-D-21), scores at each time point.
additional analysis was conducted between the CGI-S-SCA depression domain and the HAM-D-21 scores at each time point (Fig. 3). The relationship between CGI-S-SCA depressive and manic domain scores and HAM-D-17, HAM-D-21, and YMRS scores followed a linear trend. Results suggested that being considered ‘‘mildly ill’’ (CGI-S¼3) in the depression domain corresponded approximately to a HAM-D-17 score of 12 at the week 6 end point. Being considered ‘‘mildly ill’’ (CGI-S¼3) in the manic domain corresponded to a YMRS score of approximately 16 at the week 6 end point. Similarly, being considered ‘‘moderately ill’’ (CGI-S¼ 4) in the depression domain corresponded to a score of approximately 17 on HAM-D-17 at the week 6 end point. Being considered ‘‘moderately ill’’ (CGI-S¼4) in the manic domain corresponded to a score of approximately 24 on YMRS at the week 6 end point.
4. Discussion The aim of these analyses was to identify a clinically meaningful change in mood symptoms of subjects with schizoaffective disorder as measured by the HAM-D-17 and the YMRS in symptomatic subjects with schizoaffective disorder. This was identified by correlating changes in ratings on the HAM-D-17 or YMRS with those on the depressive and manic domains of the CGI-S-SCA. These analyses
assist in interpretation of published data using different scales and in identification of selection criteria for clinical trials. The large population used in this study had diverse baseline and end point scores, offering investigators a unique opportunity to identify clinically meaningful changes. Several different analyses were employed in this work so as to provide multiple lines of evidence from different approaches to support the results. Simple and multiple regression models were used to examine relationships between change scores on the HAM-D-17 and the YMRS and on the corresponding depressive or manic domains of the CGI-S-SCA. Additional simple and multiple regression models were used to explore the robustness of these relationships in subpopulations with different concomitant medication status. Ordinal logistic regression models were used to determine expected values for HAM-D-17 and YMRS scores at end point for each anchor point in the CGI-S-SCA. Linking analyses and local regression models were performed to further examine the association between CGI-S-SCA depressive and manic domain scores and HAM-D-17 and YMRS scores, respectively. Results suggest that clinically meaningful changes (1-point change in severity) in depressive and manic domains of the CGI-SSCA score corresponded to approximately 4- and 6-point absolute changes in HAM-D-17 and YMRS scores, respectively. These results are similar to those reported from a study of subjects with major depression, which indicated that a r4-point reduction in HAM-D-17 constituted no meaningful improvement in subjects (Furukawa et al., 2007). Simple and multiple regression models suggest that the overall relationship between CGI-S-SCA and mood scales is not dependent on whether subjects are receiving concomitant stable doses of antidepressants and/or mood stabilizers. Thus, although treatment can differentially affect the various symptom domains of schizoaffective disorder, the psychometric properties of these scales appear to remain constant, regardless of concomitant medication. Correlation among the scales appears to be independent of time; although subjects’ symptoms improved over the course of the study, and r2 increased over time and was highest at week 6, the overall relationship between the scales did not appear to change. It is possible that untested variables may have influenced the outcomes of the regression models. Linking analysis and local regression models suggest that the relationship between the CGI-S-SCA depressive score and the HAM-D-17 score follows a linear trend over the 6-week study period. A similar relationship was observed between the CGI-SSCA manic score and the YMRS score. The relationship between
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variables at each visit showed consistency, with increasing correlation coefficients over time. Although the linearity of the relationship between dependent and independent variables was examined using various graphic techniques, having insufficient subjects for these score ranges may have limited the linearity assumption. These results may serve as a useful guide for future research on mood disorders and schizoaffective disorders by helping to define response criteria and threshold scores for inclusion and exclusion criteria. For example, in this study, moderately ill subjects in the manic domain of schizoaffective disorder (CGIS¼4) had mean scores of approximately 24 on the YMRS, whereas moderately ill subjects in the depressive domain (CGI-S¼4) had mean HAM-D-17 scores of approximately 17. Our results are consistent with previously reported cut-off values of YMRS scores for minimal (13), mild (20), moderate (26), and severe (38) manic symptom severity levels (Young et al., 1978), and of HAM-D-17 scores for no (0 to 7), mild (8 to 13), moderate (14 to 19), severe (20 to 25), and very severe ( Z26) depressive symptoms (Rush et al., 2006). Although these are useful suggestions, they are limited in that some YMRS scores are not represented at all, and, in keeping with this approach, HAM-D-17 changes of 1 point in some cases correspond to a change in the level of severity. It is important to note that these results are based on mean data within a clinical study population. Tables 2 and 3 show that although most subjects may show correlation on the different mood scales, this will not be the case for every individual subject.
4.1. Limitations When interpreting these results, it is important to remember that the starting population had specific symptomatic inclusion criteria, and results may differ among schizoaffective subpopulations not represented in this sample. Additionally, the mood scales were not designed for assessment of symptoms of schizoaffective disorder. In particular, for the YMRS scale, active psychotic symptoms may confound assessment of mood symptoms as a certain item of the scale (specifically, item 8, which evaluates ‘‘content’’) is largely dependent on hallucinations or delusional symptoms, which are commonly observed in subjects with schizoaffective disorder. Therefore, a subject with acute psychosis may have an inflated YMRS score that does not truly represent manic symptoms. In contrast, the CGI-S manic domain specifically addresses only manic symptoms. As a result, correlations between the CGI-S manic domain score and the YMRS score may not be consistent in subjects with hallucinations or delusions. In addition, findings may differ in subjects with other mood disorder diagnoses and in populations with a broader or different distribution of symptom change scores. In this analysis, few subjects had an ‘‘extremely ill’’ CGI-S-SCA score or showed extreme improvement on CGI-S-SCA.
5. Conclusions These post hoc findings suggest that clinically meaningful changes in scores on the depressive and manic domains of the CGI-S-SCA corresponded to approximately 4- and 6-point absolute changes in HAM-D-17 and YMRS scores, respectively, in a group of symptomatic subjects with schizoaffective disorder. A linear correlation was noted over time between CGI-S-SCA depressive scores and HAM-D-17 scores, and also between CGIS-SCA manic scores and YMRS scores.
Role of funding source Funding for this study was provided by Janssen Scientific Affairs, LLC. All authors were directly involved in the design of the analysis: the collection, analysis, and interpretation of data, the writing of the report, and the decision to submit this paper for publication.
Conflict of interest I. Turkoz is an employee of Janssen Research & Development, LLC, Titusville, NJ, USA, and is a Johnson & Johnson stockholder. D.-J. Fu, C.A. Bossie, and L. Alphs are employees of Janssen Scientific Affairs, LLC, Titusville, NJ, USA, and are Johnson & Johnson stockholders. J. Sheehan was an employee of Janssen Scientific Affairs, LLC, at the time of this analysis.
Acknowledgments The authors wish to acknowledge Matthew Grzywacz, Ph.D., and Sheena Hunt, Ph.D., from ApotheCom (supported by Janssen Scientific Affairs, LLC), for providing writing and editorial assistance.
References Allen, M.H., Daniel, D.G., Revicki, D.A., Canuso, C.M., Turkoz, I., Fu, D.J., Alphs, L., Ishak, K.J., Bartko, J.J., Lindenmayer, J.P., 2012. Development and psychometric evaluation of a clinical global impression for schizoaffective disorder scale. Innovations in Clinical Neuroscience 9, 15–24. American Psychiatric Association, 2006. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association, Arlington, VA. Canuso, C.M., Lindenmayer, J.P., Kosik-Gonzalez, C., Turkoz, I., Carothers, J., Bossie, C.A., Schooler, N.R., 2010a. A randomized, double-blind, placebo-controlled study of 2 dose ranges of paliperidone extended-release in the treatment of subjects with schizoaffective disorder. Journal of Clinical Psychiatry 71, 587–598. Canuso, C.M., Schooler, N., Carothers, J., Turkoz, I., Kosik-Gonzalez, C., Bossie, C.A., Walling, D., Lindenmayer, J.P., 2010b. Paliperidone extended-release in schizoaffective disorder: a randomized, controlled study comparing a flexible dose with placebo in patients treated with and without antidepressants and/or mood stabilizers. Journal of Clinical Psychopharmacology 30, 487–495. Canuso, C.M., Turkoz, I., Fu, D.J., Bossie, C.A., 2010c. Role of paliperidone extendedrelease in treatment of schizoaffective disorder. Neuropsychiatric Diseases and Treatment 6, 667–679. Furukawa, T.A., Akechi, T., Azuma, H., Okuyama, T., Higuchi, T., 2007. Evidencebased guidelines for interpretation of the Hamilton rating scale for depression. Journal of Clinical Psychopharmacology 27, 531–534. Guy, W., 1976. ECDEU Assessment Manual for Psychopharmacology (028 Clinical Global Impressions [CGI]). pp. 218–222. Hamilton, M., 1967. Development of a rating scale for primary depressive illness. British Journal of Social and Clinical Psychology 6, 278–296. Haro, J.M., Kamath, S.A., Ochoa, S., Novick, D., Rele, K., Fargas, A., Rodriguez, M.J., Rele, R., Orta, J., Kharbeng, A., Araya, S., Gervin, M., Alonso, J., Mavreas, V., Lavrentzou, E., Liontos, N., Gregor, K., Jones, P.B., 2003. The clinical global impression-schizophrenia scale: a simple instrument to measure the diversity of symptoms present in schizophrenia. Acta Psychiatrica Scandinavica Supplement, 16–23. Kemp, D.E., Johnson, E., Wang, W.V., Tohen, M., Calabrese, J.R., 2011. Clinical utility of early improvement to predict response or remission in acute mania: focus on olanzapine and risperidone. Journal of Clinical Psychiatry 72, 1236–1241. Leucht, S., Kane, J.M., Etschel, E., Kissling, W., Hamann, J., Engel, R.R., 2006. Linking the PANSS, BPRS, and CGI: clinical implications. Neuropsychopharmacology 31, 2318–2325. Leucht, S., Kane, J.M., Kissling, W., Hamann, J., Etschel, E., Engel, R., 2005a. Clinical implications of brief psychiatric rating scale scores. British Journal of Psychiatry 187, 366–371. Leucht, S., Kane, J.M., Kissling, W., Hamann, J., Etschel, E., Engel, R.R., 2005b. What does the PANSS mean? Schizophrenia Research 79, 231–238. Price, L.R., Lurie, A., Wilkins, C., 2001. Computer program exchange: EQUIPERCENT: a SAS program for calculating equivalent scores using the equipercentile method. Applied Psychological Measurement 25, 332. Rush, A.J., Trivedi, M.H., Wisniewski, S.R., Nierenberg, A.A., Stewart, J.W., Warden, D., Niederehe, G., Thase, M.E., Lavori, P.W., Lebowitz, B.D., McGrath, P.J., Rosenbaum, J.F., Sackeim, H.A., Kupfer, D.J., Luther, J., Fava, M., 2006. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STARnD report. American Journal of Psychiatry 163, 1905–1917. Spearing, M.K., Post, R.M., Leverich, G.S., Brandt, D., Nolen, W., 1997. Modification of the Clinical Global Impressions (CGI) scale for use in bipolar illness (BP): the CGI-BP. Psychiatry Research 73, 159–171. Vieta, E., Goikolea, J.M., Corbella, B., Benabarre, A., Reinares, M., Martinez, G., Fernandez, A., Colom, F., Martinez-Aran, A., Torrent, C., 2001. Risperidone safety and efficacy in the treatment of bipolar and schizoaffective disorders: results from a 6-month, multicenter, open study. Journal of Clinical Psychiatry 62, 818–825. Young, R.C., Biggs, J.T., Ziegler, V.E., Meyer, D.A., 1978. A rating scale for mania: reliability, validity and sensitivity. British Journal of Psychiatry 133, 429–435.
Contents lists available at SciVerse ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Review
Relationship between the clinical global impression of severity for schizoaffective disorder scale and established mood scales for mania and depression$ Ibrahim Turkoz a,n, Dong-Jing Fu b, Cynthia A. Bossie b, John J. Sheehan b,c, Larry Alphs b a
Janssen Research & Development, LLC, 1125 Trenton-Harbourton Road, Titusville, NJ 08650, USA Janssen Scientific Affairs, LLC, Titusville, NJ, USA c Bristol-Myers Squibb, Plainsboro, NJ, USA b
a r t i c l e i n f o
abstract
Article history: Received 21 December 2012 Accepted 30 January 2013 Available online 18 March 2013
Background: This analysis explored the relationship between ratings on HAM-D-17 or YMRS and those on the depressive or manic subscale of CGI-S for schizoaffective disorder (CGI-S-SCA). Methods: This post hoc analysis used the database (N ¼ 614) from two 6-week, randomized, placebocontrolled studies of paliperidone ER versus placebo in symptomatic subjects with schizoaffective disorder assessed using HAM-D-17, YMRS, and CGI-S-SCA scales. Parametric and nonparametric regression models explored the relationships between ratings on YMRS and HAM-D-17 and on depressive and manic domains of the CGI-S-SCA from baseline to the 6-week end point. A clinically meaningful improvement was defined as a change of 1 point in the CGI-S-SCA score. No adjustment was made for multiplicity. Results: Multiple linear regression models suggested that a 1-point change in the depressive domain of CGI-S-SCA corresponded to an average 3.6-point (SE ¼0.2) change in HAM-D-17 score. Similarly, a 1-point change in the manic domain of CGI-S-SCA corresponded to an average 5.8-point (SE ¼ 0.2) change in YMRS score. Results were confirmed using local and cumulative logistic regression models in addition to equipercentile linking. Limitations: Lack of subjects scoring over the complete range of possible scores may limit broad application of the analyses. Conclusion: Clinically meaningful score changes in depressive and manic domains of CGI-S-SCA corresponded to approximately 4- and 6-point score changes on HAM-D-17 and YMRS, respectively, in symptomatic subjects with schizoaffective disorder. & 2013 Elsevier B.V. All rights reserved.
Keywords: Schizoaffective disorder Clinical global impression-severityschizoaffective disorder Hamilton rating scale-depression, 17-Item version Young mania rating scale
Contents 1. 2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 2.1. Study design. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 2.2. Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 3.1. Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 3.2. Clinically meaningful changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 3.2.1. CGI-S-SCA depressive domain and HAM-D-17 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 3.2.2. CGI-SCA mania domain and YMRS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 3.3. Sensitivity analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
$ Prior presentation: Parts of these data were previously presented as a poster at the 7th Annual International Society for CNS Clinical Trials and Methodology Scientific Meeting, February 21–23, 2011, Washington, DC, and the 51st Annual New Clinical Drug Evaluation Unit Meeting, June 13–16, 2011, Boca Raton, FL, USA. n Corresponding author. Tel.: þ609 730 7719; fax: þ 609 730 3125. E-mail address: [email protected] (I. Turkoz).
0165-0327/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2013.01.047
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4.
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 4.1. Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
1. Introduction Schizoaffective disorder identifies a clinical entity whose symptoms encompass criteria for schizophrenia, as well as for a major depressive, manic, or mixed episode (American Psychiatric Association, 2006). Studies of schizoaffective disorder have traditionally used a combination of scales designed to assess schizophrenia or mood disorders, such as the Positive and Negative Syndrome Scale (PANSS), the Young Mania Rating Scale (YMRS, Young et al., 1978), and the Hamilton Rating Scale-Depression, 17- and 21-item versions (HAM-D-17 and HAM-D-21) (Hamilton, 1967, Vieta et al., 2001). Although these scales are used to measure schizoaffective disorder in clinical trial settings, clinically meaningful changes in scale scores on these instruments are not well established. Data are often evaluated as change scores, as percent reductions, or in relation to a predefined threshold score. YMRS scores of approximately 13, 20, 26, and 38 have been suggested to correspond to minimal, mild, moderate, and severe manic symptom severity levels, respectively (Young et al., 1978). In a comparison of acute and longer-term treatment outcomes of the Sequenced Treatment Alternatives to Relieve Depression trial, HAM-D-17 scores of 0 to 7, 8 to 13, 14 to 19, 20 to 25, and 26 and higher corresponded to no, mild, moderate, severe, and very severe depressive symptoms, respectively (Rush et al., 2006). Although these data may facilitate approximation of what might be considered a meaningful change score, such interpretation is limited. For example, from the HAM-D data, a 1-point change could shift categories of severity but is unlikely to be considered a clinically relevant change. A meta-analysis of seven trials of major depressive disorder suggests that a 4-point or less reduction in HAM-D-17 score indicated no improvement in symptomatic subjects (Furukawa et al., 2007). Several other publications have examined relationships between various psychiatric scales with the intent of helping to define clinically meaningful changes. For example, a correlation was reported between Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression (CGI) ratings in symptomatic subjects with schizophrenia (Leucht et al., 2005a). A CGI-Improvement (CGI-I) rating of ‘‘minimal improvement’’ was associated with BPRS reductions between 1 and 4 weeks of treatment of 24% to 30%, whereas a rating of ‘‘much improved’’ corresponded to BPRS reductions of 44% to 58% (Leucht et al., 2005a). In another study of subjects with schizophrenia, Leucht et al. reported that a reduction in PANSS of approximately 50% corresponded to a ‘‘much improved’’ CGI-I rating (Leucht et al., 2005b). Furthermore, an equipercentile linking analysis of PANSS, BPRS, and CGI ratings from 14 drug trials in acutely ill subjects with schizophrenia reported that an absolute reduction in BPRS/PANSS by 10–15 points corresponded to a CGI-I of ‘‘minimally improved’’ and to a change in the CGI-S score of 1 point (Leucht et al., 2006). However, such a change is highly dependent on initial scores at baseline. Published reports describing clinically meaningful changes in CGI-S with the commonly used mood scales, YMRS and HAM-D, are limited and have not discussed the schizoaffective population (Kemp et al., 2011; Furukawa et al., 2007).
The Clinical Global Impression-Severity (CGI-S) scale has been widely used to measure clinical outcomes in symptom severity and treatment efficacy in subjects with psychoses (Guy, 1976). This scale has ratings from 1 (not ill) to 7 (extremely ill) (Guy, 1976), and, empirically, a change of 1 or more points on the CGI-S can be considered clinically meaningful. Change on this scale has strong face validity, and the usefulness of this measurement approach is reflected in the fact that many disorder-specific CGI scales have been introduced into clinical trials, among them the CGI for schizophrenia (CGI-SCH) (Haro et al., 2003), for bipolar disorder (CGI-BP) (Spearing et al., 1997), and, more recently, for schizoaffective disorder (CGI-S-SCA). The latter includes ratings of severity of the four schizoaffective disorder domains (positive, negative, manic, and depressive), plus an overall rating (Allen et al., 2012). This analysis explored the relationships between ratings on both the HAM-D-17 and the YMRS and those on the depressive and manic domains of the CGI-S-SCA, to determine which change score on the mood scales corresponds to a 1-point (i.e., clinically meaningful) change on the CGI-S-SCA in subjects with schizoaffective disorder (Canuso et al., 2010a, 2010b, 2010c).
2. Methods 2.1. Study design This post hoc analysis used a database (N ¼614) composed of two six-week, randomized, placebo-controlled studies of paliperidone ER treatment versus placebo in subjects with schizoaffective disorder (Canuso et al., 2010a, 2010b, 2010c), which included similar subject populations and study designs (NCT00412373, NCT00397033). All subjects had been given a confirmed diagnosis of schizoaffective disorder based on the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV-TR), Disorders (SCID). Subjects had an acute exacerbation of schizoaffective disorder, with YMRS and/or HAM-D-21 scores Z16 and PANSS total scores Z60 (plus scores Z4 on Z2 PANSS items [hostility, excitement, tension, uncooperativeness, and poor impulse control]). Subjects were permitted to receive concomitant treatment with mood stabilizers and/or antidepressants, provided these medications had been given at a stable dose within 30 days of screening. Assessments for the original studies included the HAM-D-21, YMRS, PANSS total, and CGI-S-SCA (overall score and manic and depressive domains). These were assessed at baseline, day 4, and weeks 1, 2, 3, 4, and 6 (end point). Ratings on these scales were based on symptoms during the week before the assessment visit. To focus on the core symptoms of depression, only the first 17 (HAM-D-17) of the 21 items of the HAM-D-21 scale were used in this post hoc analysis. All raters had clinical and/or research experience with this subject population, had participated in study-specific training, and had passed required certification for the scales. Whenever possible, the same raters at each site assessed the same subjects throughout the study.
I. Turkoz et al. / Journal of Affective Disorders 150 (2013) 17–22
2.2. Statistical analysis The intent-to-treat population used for this analysis included randomly assigned subjects who received at least one dose of study medication and at least one postbaseline efficacy evaluation. Clinically meaningful change was defined as a 1-point change in the CGI-S-SCA scale score. Simple and multiple (with explanatory study design variables for treatment, protocol, concomitant medication strata, and baseline score) regression models explored relationships between change scores on the HAM-D-17 and the YMRS and the depressive or the manic domain of the CGI-S-SCA scale, respectively, from baseline to the week 6 end point, as continuous dependent variables. Assumptions such as a linear relationship between variables and equal variances of error terms were evaluated using residual plots. Regression coefficients and r2 were calculated at each visit in addition to week 6 end point to support the consistency of observed estimates over time. Additional simple and multiple regression models were used to explore relationships between HAM-D-17 and YMRS and CGI-S-SCA depressive and manic domain scores from baseline to end point by concomitant medication status (with or without antidepressants and/or mood stabilizers). No adjustment was made for multiplicity. Ordinal logistic regression models were used to determine expected values of HAM-D-17 and YMRS at end point for each anchor point in the CGI-S-SCA. Additional logistic regression models were fitted using the change score of CGI-S-SCA as a categorical variable. Categories of change in CGI-S-SCA were defined as improved (severity score lowered one or more units), unchanged (0), or worsening (severity score increased by one or more units). Both YMRS and HAM-D-17 scores were also categorized. YMRS cut-off values were minimal (13), mild (20),
Simple regression Multiple regression
moderate (26), and severe (38) manic symptoms (Young et al., 1978), and HAM-D-17 cut-off scores were no (0 to 7), mild (8 to 13), moderate (14 to 19), severe (20 to 25), and very severe ( Z26) depressive symptoms (Rush et al., 2006). Predicted probabilities of CGI-S scores were computed for given YMRS and HAM-D cut-off points. Sensitivity analysis is an essential element in model building. Both equipercentile linking analysis and local regression approaches were employed. Equipercentile linking analysis (Price et al., 2001) was performed to determine the correspondence of CGI-S-SCA depressive domain scores to HAM-D-17 and HAM-D-21 scores, and of CGI-S-SCA manic domain scores to YMRS scores. Percentiles of the cumulative distribution of observed values for the two scales were mapped by the method of Leucht (Leucht et al., 2005b). Briefly, the equipercentile equating involved first determining percentile ranks for the relevant domain of CGI-S-SCA and HAM-D-17, HAM-D-21, or YMRS. Second, individual scores on the CGI-S-SCA scale and on the relevant mood scale with equipercentile rank were matched together. Equipercentile equating defines a nonlinear relationship between score scales by setting the percentile ranks equal for each point. Local regression models were conducted to allow greater flexibility than is seen with traditional modeling tools—an approach used in situations in which a suitable parametric form of the regression surface is not known. This approach is also appropriate when outliers are noted in the data and a robust fitting method is necessary.
3. Results 3.1. Subjects
Least squares estimates of HAM-D-17 point change (SE)
P value
r2
4.4 (0.2) 3.6 (0.2)
o 0.001 o 0.001
0.516 0.589
Least squares estimates of YMRS point change (SE)
P value
r2
Baseline demographic and clinical characteristics and improvement in efficacy measures from baseline to end point have been reported previously (Canuso et al., 2010a, 2010b, 2010c). Subjects’ mean age was 37 years, and 60% were male. The schizoaffective disorder type was bipolar in 69% of subjects and depressive in 31%. Nearly half of subjects (45%) were taking mood stabilizers and/or antidepressants. At baseline, subjects had a mean (standard deviation [SD]) YMRS score of 24.4 (10.0), a mean (SD) HAM-D-17 score of 16.8 (8.0), and mean (SD) CGI-S depression and manic domain scores of 3.2 (1.5) and 3.5 (1.5), respectively (Canuso et al., 2010c).
6.6 (0.2) 5.8 (0.2)
o 0.001 o 0.001
0.630 0.675
3.2. Clinically meaningful changes
Table 1 HAM-D-17 and YMRS changes associated with a 1-point change in CGI-S-SCA depressive and manic domains from baseline to endpoint.
Simple regression Multiple regression
19
Testing the hypothesis that the corresponding least squares estimates are equal to 0. P-valueo 0.05 indicates that there is strong evidence that the slope is not equal to 0. CGI-S-SCA: Clinical Global Impression-Schizoaffective Disorder, HAM-D-17: Hamilton Rating Scale-Depression, 17-item version, SE: standard error, YMRS: Young Mania Rating Scale.
3.2.1. CGI-S-SCA depressive domain and HAM-D-17 Results from simple and multiple regression models for CGI-SSCA depressive domain and HAM-D-17 are shown in Table 1. At the study end point, the simple regression model suggested that a 1-point change in score for the CGI-S-SCA depressive
Table 2 Distribution of HAM-D-17 scores by CGI-S-SCA depressive domain score at week 6 end point. Probabilities Z20% are highlighted in italic. Predictive probability of HAM-D-17 score at end point (%)
CGI-S-SCA depressive domain
0–7 n¼ 291
8–13 n ¼150
14–19 n ¼96
20–25 n ¼49
Z26 n ¼27
CGI-S-SCA ¼1 normal CGI-S-SCA ¼2 minimally ill CGI-S-SCA ¼3 mildly ill CGI-S-SCA ¼4 moderately ill CGI-S-SCA ¼5 markedly ill CGI-S-SCA ¼6/7 severely ill/extremely severely ill
62.9 23.7 11.3 1.4 0.7 0
19.3 26.7 44.7 8.0 1.3 0
5.2 12.5 41.7 36.5 4.2 0
0 0 14.3 59.2 20.4 6.1
0 0 0 25.9 51.9 22.2
Ordinal logistic regression model with HAM-D-17as a predictor (odds ratio: 1.36; 95% CI: 1.31 to 1.40). CGI-S-SCA: Clinical Global Impression-Severity-Schizoaffective Disorder, HAM-D-17: Hamilton Rating Scale-Depression, 17-item version.
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CGI-S-SCA mania domain corresponds to a least squares estimate of a 6.6-point (SE¼0.2) change in the YMRS. The multiple regression model identified this change to be 5.8 points (SE¼0.2) on the YMRS. The regression coefficient ranged between 5.0 and 6.6 units. The observed r2 ranged between 0.45 and 0.63, with numerically increasing values observed over time, and the highest value observed at week 6. These results suggest that the relationship between the two variables (CGI-S-SCA manic domain and YMRS) was consistent at each visit starting from week 1. The relationship between CGI-S-SCA and YMRS did not differ between subjects taking antidepressants and/or mood stabilizers and subjects receiving paliperidone ER monotherapy. Simple regression model-determined changes in scores for the CGI-S of manic symptoms from baseline to end point were 6.2 and 6.8, and r2 was 0.61 and 0.64, for subjects with and without concomitant medications, respectively. The logistic regression model-determined changes in the CGIS-SCA manic domain categories suggested an average 30% probability of a shift of one category at end point when the YMRS score changed by 1 point. Predictive probabilities of changes in the YMRS score for each CGI-S-SCA manic score are outlined in Table 3.
domain corresponded to an average least squares estimate of a 4.4-point (standard error [SE] ¼0.2) change in the HAM-D-17 score, whereas a multiple regression model suggested correspondence to an average least square estimate of a 3.6-point (SE ¼0.2) change in the HAM-D-17 score. The regression coefficient from least squares ranged between 3.9 and 4.4 units based on simple regression analysis. The observed r2 ranged from 0.45 to 0.52, with numerically increasing values observed over time, and the highest value observed at week 6. These results suggest that the relationship between the two variables (CGI-S-SCA depressive domain and HAM-D-17) was consistent at each visit. The overall relationship between CGI-S-SCA and HAM-D-17 did not differ between subjects taking antidepressants and/or mood stabilizers compared with those not taking concomitant medications. The simple regression analysis identified that changes in CGI-S depressive symptoms from baseline to end point for subjects with and without concomitant medications were 4.3 and 4.5, and r2 was 0.48 and 0.55, respectively. The logistic regression model with the CGI-S-SCA depressive domain categories of change suggested an average 36% probability of a shift of one category at end point when the HAM-D-17 score changed by 1 point. The predictive probability of the HAM-D-17 score range for each CGI-S-SCA depressive score is outlined in Table 2.
3.3. Sensitivity analysis 3.2.2. CGI-SCA mania domain and YMRS Results from simple and multiple regression models for the CGI-S-SCA mania domain and YMRS are shown in Table 1. A simple regression model suggests that a 1-point change in the
Figs. 1 and 2 show the equipercentile linking analyses and local regression models conducted between CGI-S-SCA depression and manic domain scores and HAM-D-17 and YMRS scores at each time point. For reference and sensitivity purposes, an
Table 3 Distribution of YMRS scores by CGI-S-SCA manic domain score at week 6 end point. Probabilities Z 20% are highlighted in italic. Predictive probability of YMRS score at end point (%)
CGI-S-SCA manic domain
0–7 n ¼202
8–12 n ¼113
13–19 n¼129
20–25 n¼ 74
26–37 n ¼71
Z 38 n¼ 24
CGI-S-SCA ¼1 normal CGI-S-SCA ¼2 minimally ill CGI-S-SCA ¼3 mildly ill CGI-S-SCA ¼4 moderately ill CGI-S-SCA ¼5 markedly ill CGI-S-SCA ¼6/7 severely ill/extremely severely ill
73.3 21.8 5.0 0 0 0
28.3 41.6 23.9 6.2 0 0
16.3 21.7 47.3 13.2 0.8 0.8
8.1 4.1 33.8 44.6 9.5 0
0 1.4 8.5 32.4 42.3 15.5
0 0 4.2 0 58.3 37.5
Extremely ill 7
Extremely ill 7
Severely ill 6
Severely ill 6
Markedly ill 5
Moderately ill 4 Baseline (N = 614) Day 4 (n = 609) Week 1 (n = 579) Week 2 (n = 508) Week 3 (n = 452) Week 4 (n = 429) Week 6 (n = 392)
Mildly ill 3
Minimally ill 2
Normal 1
CGI-S-SCA Depressive Domain Score
CGI-S-SCA Depressive Domain Score
Ordinal logistic regression model with YMRS as a predictor (odds ratio: 1.30; 95% CI: 1.26 to 1.33). CGI-S-SCA: Clinical Global Impression-Severity-Schizoaffective Disorder. YMRS: Young Mania Rating Scale.
Markedly ill 5
Moderately ill 4 Baseline (N = 614) Day 4 (n = 609) Week 1 (n = 579) Week 2 (n = 508) Week 3 (n = 452) Week 4 (n = 429) Week 6 (n = 392)
Mildly ill 3
Minimally ill 2
Normal 1 0
5
10
15
20
25
HAM-D-17 Total Score
30
35
40
0
5
10
15
20
25
30
35
40
HAM-D-17 Total Score
Fig. 1. Equipercentile linking (A) and local regression model (B) results between Clinical Global Impression-Severity-Schizoaffective Disorder (CGI-S-SCA) depression domain and Hamilton Rating Scale-Depression, 17-item version (HAM-D-17), scores at each time point.
Extremely ill 7
Extremely ill 7
Severely ill 6
Severely ill 6
Markedly ill 5
Moderately ill 4 Baseline (N = 614) Day 4 (n = 609) Week 1 (n = 579) Week 2 (n = 508) Week 3 (n = 452) Week 4 (n = 429) Week 6 (n = 392)
Mildly ill 3
Minimally ill 2
CGI-S-SCA Manic Domain Score
CGI-S-SCA Manic Domain Score
I. Turkoz et al. / Journal of Affective Disorders 150 (2013) 17–22
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Markedly ill 5
Moderately ill 4 Baseline (N = 614) Day 4 (n = 609) Week 1 (n = 579) Week 2 (n = 508) Week 3 (n = 452) Week 4 (n = 429) Week 6 (n = 392)
Mildly ill 3
Minimally ill 2
Normal 1
Normal 1 0
5
10
15
20
25
30
35
40
45
50
YMRS Total Score
0
5
10
15
20
25
30
35
40
45
50
YMRS Total Score
Fig. 2. Equipercentile linking (A) and local regression model (B) results between Clinical Global Impression-Severity-Schizoaffective Disorder (CGI-S-SCA) manic domain and Young Mania Rating Scale (YMRS) scores at each time point.
CGI-S-GCA Depressive Domain Score
Extremely ill 7
Severely ill 6
Markedly ill 5
Moderately ill 4 Baseline (N = 614) Day 4 (n = 609) Week 1 (n = 579) Week 2 (n = 508) Week 3 (n = 452) Week 4 (n = 429) Week 6 (n = 392)
Mildly ill 3
Minimally ill 2
Normal 1 0
5
10
15
20
25
30
35
40
45
HAM-D-21 Total Score
Fig. 3. Equipercentile linking results between Clinical Global Impression-SeveritySchizoaffective Disorder (CGI-S-SCA) depression domain and Hamilton Rating Scale-Depression, 21-item version (HAM-D-21), scores at each time point.
additional analysis was conducted between the CGI-S-SCA depression domain and the HAM-D-21 scores at each time point (Fig. 3). The relationship between CGI-S-SCA depressive and manic domain scores and HAM-D-17, HAM-D-21, and YMRS scores followed a linear trend. Results suggested that being considered ‘‘mildly ill’’ (CGI-S¼3) in the depression domain corresponded approximately to a HAM-D-17 score of 12 at the week 6 end point. Being considered ‘‘mildly ill’’ (CGI-S¼3) in the manic domain corresponded to a YMRS score of approximately 16 at the week 6 end point. Similarly, being considered ‘‘moderately ill’’ (CGI-S¼ 4) in the depression domain corresponded to a score of approximately 17 on HAM-D-17 at the week 6 end point. Being considered ‘‘moderately ill’’ (CGI-S¼4) in the manic domain corresponded to a score of approximately 24 on YMRS at the week 6 end point.
4. Discussion The aim of these analyses was to identify a clinically meaningful change in mood symptoms of subjects with schizoaffective disorder as measured by the HAM-D-17 and the YMRS in symptomatic subjects with schizoaffective disorder. This was identified by correlating changes in ratings on the HAM-D-17 or YMRS with those on the depressive and manic domains of the CGI-S-SCA. These analyses
assist in interpretation of published data using different scales and in identification of selection criteria for clinical trials. The large population used in this study had diverse baseline and end point scores, offering investigators a unique opportunity to identify clinically meaningful changes. Several different analyses were employed in this work so as to provide multiple lines of evidence from different approaches to support the results. Simple and multiple regression models were used to examine relationships between change scores on the HAM-D-17 and the YMRS and on the corresponding depressive or manic domains of the CGI-S-SCA. Additional simple and multiple regression models were used to explore the robustness of these relationships in subpopulations with different concomitant medication status. Ordinal logistic regression models were used to determine expected values for HAM-D-17 and YMRS scores at end point for each anchor point in the CGI-S-SCA. Linking analyses and local regression models were performed to further examine the association between CGI-S-SCA depressive and manic domain scores and HAM-D-17 and YMRS scores, respectively. Results suggest that clinically meaningful changes (1-point change in severity) in depressive and manic domains of the CGI-SSCA score corresponded to approximately 4- and 6-point absolute changes in HAM-D-17 and YMRS scores, respectively. These results are similar to those reported from a study of subjects with major depression, which indicated that a r4-point reduction in HAM-D-17 constituted no meaningful improvement in subjects (Furukawa et al., 2007). Simple and multiple regression models suggest that the overall relationship between CGI-S-SCA and mood scales is not dependent on whether subjects are receiving concomitant stable doses of antidepressants and/or mood stabilizers. Thus, although treatment can differentially affect the various symptom domains of schizoaffective disorder, the psychometric properties of these scales appear to remain constant, regardless of concomitant medication. Correlation among the scales appears to be independent of time; although subjects’ symptoms improved over the course of the study, and r2 increased over time and was highest at week 6, the overall relationship between the scales did not appear to change. It is possible that untested variables may have influenced the outcomes of the regression models. Linking analysis and local regression models suggest that the relationship between the CGI-S-SCA depressive score and the HAM-D-17 score follows a linear trend over the 6-week study period. A similar relationship was observed between the CGI-SSCA manic score and the YMRS score. The relationship between
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variables at each visit showed consistency, with increasing correlation coefficients over time. Although the linearity of the relationship between dependent and independent variables was examined using various graphic techniques, having insufficient subjects for these score ranges may have limited the linearity assumption. These results may serve as a useful guide for future research on mood disorders and schizoaffective disorders by helping to define response criteria and threshold scores for inclusion and exclusion criteria. For example, in this study, moderately ill subjects in the manic domain of schizoaffective disorder (CGIS¼4) had mean scores of approximately 24 on the YMRS, whereas moderately ill subjects in the depressive domain (CGI-S¼4) had mean HAM-D-17 scores of approximately 17. Our results are consistent with previously reported cut-off values of YMRS scores for minimal (13), mild (20), moderate (26), and severe (38) manic symptom severity levels (Young et al., 1978), and of HAM-D-17 scores for no (0 to 7), mild (8 to 13), moderate (14 to 19), severe (20 to 25), and very severe ( Z26) depressive symptoms (Rush et al., 2006). Although these are useful suggestions, they are limited in that some YMRS scores are not represented at all, and, in keeping with this approach, HAM-D-17 changes of 1 point in some cases correspond to a change in the level of severity. It is important to note that these results are based on mean data within a clinical study population. Tables 2 and 3 show that although most subjects may show correlation on the different mood scales, this will not be the case for every individual subject.
4.1. Limitations When interpreting these results, it is important to remember that the starting population had specific symptomatic inclusion criteria, and results may differ among schizoaffective subpopulations not represented in this sample. Additionally, the mood scales were not designed for assessment of symptoms of schizoaffective disorder. In particular, for the YMRS scale, active psychotic symptoms may confound assessment of mood symptoms as a certain item of the scale (specifically, item 8, which evaluates ‘‘content’’) is largely dependent on hallucinations or delusional symptoms, which are commonly observed in subjects with schizoaffective disorder. Therefore, a subject with acute psychosis may have an inflated YMRS score that does not truly represent manic symptoms. In contrast, the CGI-S manic domain specifically addresses only manic symptoms. As a result, correlations between the CGI-S manic domain score and the YMRS score may not be consistent in subjects with hallucinations or delusions. In addition, findings may differ in subjects with other mood disorder diagnoses and in populations with a broader or different distribution of symptom change scores. In this analysis, few subjects had an ‘‘extremely ill’’ CGI-S-SCA score or showed extreme improvement on CGI-S-SCA.
5. Conclusions These post hoc findings suggest that clinically meaningful changes in scores on the depressive and manic domains of the CGI-S-SCA corresponded to approximately 4- and 6-point absolute changes in HAM-D-17 and YMRS scores, respectively, in a group of symptomatic subjects with schizoaffective disorder. A linear correlation was noted over time between CGI-S-SCA depressive scores and HAM-D-17 scores, and also between CGIS-SCA manic scores and YMRS scores.
Role of funding source Funding for this study was provided by Janssen Scientific Affairs, LLC. All authors were directly involved in the design of the analysis: the collection, analysis, and interpretation of data, the writing of the report, and the decision to submit this paper for publication.
Conflict of interest I. Turkoz is an employee of Janssen Research & Development, LLC, Titusville, NJ, USA, and is a Johnson & Johnson stockholder. D.-J. Fu, C.A. Bossie, and L. Alphs are employees of Janssen Scientific Affairs, LLC, Titusville, NJ, USA, and are Johnson & Johnson stockholders. J. Sheehan was an employee of Janssen Scientific Affairs, LLC, at the time of this analysis.
Acknowledgments The authors wish to acknowledge Matthew Grzywacz, Ph.D., and Sheena Hunt, Ph.D., from ApotheCom (supported by Janssen Scientific Affairs, LLC), for providing writing and editorial assistance.
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