Journal of Affective Disorders 150 (2013) 1722

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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 Scientic 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 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 dened 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 0.2) 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 0.2)
change in YMRS score. Results were conrmed 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 Scientic
Meeting, February 2123, 2011, Washington, DC, and the 51st Annual New Clinical Drug Evaluation Unit Meeting, June 1316, 2011, Boca Raton, FL, USA.
n
Corresponding author. Tel.: 609 730 7719; fax: 609 730 3125.
E-mail address: ITurkoz@its.jnj.com (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

18

I. Turkoz et al. / Journal of Affective Disorders 150 (2013) 1722

4.

Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
4.1.
Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Conict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

1. Introduction
Schizoaffective disorder identies 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 predened 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
dene 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 1015
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 efcacy 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
reected in the fact that many disorder-specic 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 614) 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 conrmed 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 rst 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-specic training, and had passed required certication 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) 1722

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 efcacy evaluation.
Clinically meaningful change was dened 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 coefcients 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 tted using the change score of CGI-S-SCA as a
categorical variable. Categories of change in CGI-S-SCA were
dened 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). Briey, the equipercentile equating involved rst 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 denes a
nonlinear relationship between score scales by setting the percentile ranks equal for each point. Local regression models were
conducted to allow greater exibility than is seen with traditional
modeling toolsan 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 tting 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 efcacy 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

07
n 291

813
n 150

1419
n 96

2025
n 49

Z26
n 27

CGI-S-SCA 1 normal
CGI-S-SCA 2 minimally ill
CGI-S-SCA 3 mildly ill
CGI-S-SCA 4 moderately ill
CGI-S-SCA 5 markedly ill
CGI-S-SCA 6/7 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.

20

I. Turkoz et al. / Journal of Affective Disorders 150 (2013) 1722

CGI-S-SCA mania domain corresponds to a least squares estimate

of a 6.6-point (SE0.2) change in the YMRS. The multiple
regression model identied this change to be 5.8 points
(SE0.2) on the YMRS.
The regression coefcient 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] 0.2) 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 0.2)
change in the HAM-D-17 score.
The regression coefcient 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 identied 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

07
n 202

812
n 113

1319
n129

2025
n 74

2637
n 71

Z 38
n 24

CGI-S-SCA 1 normal
CGI-S-SCA 2 minimally ill
CGI-S-SCA 3 mildly ill
CGI-S-SCA 4 moderately ill
CGI-S-SCA 5 markedly ill
CGI-S-SCA 6/7 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

10

15

20

25

HAM-D-17 Total Score

30

35

40

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) 1722

21

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

10

15

20

25

30

35

40

45

50

YMRS Total Score

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

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-S3) 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-S3) in the manic domain corresponded to a YMRS score of approximately 16 at the week 6 end
point. Similarly, being considered moderately ill (CGI-S 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-S4) 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 identied 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

identication 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
inuenced 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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I. Turkoz et al. / Journal of Affective Disorders 150 (2013) 1722

variables at each visit showed consistency, with increasing

correlation coefcients over time. Although the linearity of the
relationship between dependent and independent variables was
examined using various graphic techniques, having insufcient
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
dene 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 (CGIS4) had mean scores of approximately 24 on the YMRS, whereas
moderately ill subjects in the depressive domain (CGI-S4) 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 specic 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 (specically, 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 inated
YMRS score that does not truly represent manic symptoms. In
contrast, the CGI-S manic domain specically 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, ndings 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 ndings 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 Scientic 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.

Conict 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 Scientic Affairs, LLC, Titusville, NJ, USA, and are Johnson
& Johnson stockholders. J. Sheehan was an employee of Janssen Scientic 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 Scientic Affairs, LLC), for providing
writing and editorial assistance.

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