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2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
ACTA PSYCHIATRICA SCANDINAVICA
L. Tondo1,2, G. H. V
azquez1,3,
C. Baethge4, C. Baronessa5,
L. Bolzani5, A. Koukopoulos6,7,
L. Mazzarini6, A. Murru8, I.
Pacchiarotti8, M. Pinna2, P.
Salvatore1,9, G. Sani6,7, V. Selle5,
G. Spalletta10,11, P. Girardi6,7,
M. Tohen12, E. Vieta8, R. J.
Baldessarini1
1
Tondo et al.
Signicant outcomes
We
identied 12 factors showing signicant dierences among three DSM-IV psychotic illnesses
(bipolar disorder with psychotic features, schizoaective disorder, and schizophrenia). Of these, ve
were demographic: sex, current age, educational level, occupational, and marital status, and seven
were clinical: family history of bipolar disorder, cyclothymic or hyperthymic temperament, age at illness onset, stressors associated with illness onset, substance abuse, suicidal acts or ideation, and suicidal acts only.
Nine factors signicantly dierentiated subjects diagnosed with bipolar disorder from those with
schizoaective disorder.
Nine factors signicantly dierentiated those with schizoaective disorder from those with schizophrenia.
All 12 factors were signicantly dierent between cases of bipolar disorder vs. schizophrenia.
Factors associated with social, interpersonal, and occupational outcomes were consistently deemed
to be more favorable with bipolar disorder than in the other diagnostic groups.
Limitations
Generalizability of ndings to other settings may be limited despite the large aggregate sample from
geographically and culturally diverse sites.
Introduction
Diagnostic comparisons
to imply a more or less chronic disorder with similarities to SZ (possibly with depression-prone and
excitement-prone subtypes; DSM-III, and DSMIV), or to belong within a group of schizophrenia
spectrum and other psychotic disorders (DSM-5)
(13). Not surprisingly, a recent systematic review
and meta-analysis aimed at comparing demographic and clinical descriptors in SA disorder
patients with those of SZ and BD concluded that
SA disorder may be somewhat closer to schizophrenia than to BD, although when only patients
with psychotic BD were considered, dierences
among the three groups were less evident (14). This
nding may reect DSM-IV and DSM-5 diagnostic criteria for SA which categorize the disorder
among the schizophrenia-related disorders. Nevertheless, the concept of a third major group of psychotic disorders that shares features of both BD
and SZ continues to be unresolved and of interest
(11, 1416), despite proposals that the category
simply be abandoned as insuciently dened (17,
18).
The conceptualization, characteristics, and
course of a possible SA category, as well as its distinction from BDp and from SZ, remain inadequately dened, in part reecting lack of consensus
on its basic characteristics. The importance of longitudinal diagnostic evaluation of patients with
psychotic disorder, and the critical inuence of
diagnostic criteria, was underscored in the
McLean-Harvard First Episode Project, in which
most DSM-IV-TR-based diagnoses of SA disorder
arose due to identication of aective features over
1224 months among cases presenting initially as a
psychotic illness (19). Given the incompletely
resolved characteristics, similarities, and dierences among persons considered to have BDp, SA,
or SZ, we compared selected sociodemographic
and clinical variables in a large sample of patients
diagnosed by DSM-IV-TR criteria with these three
conditions, sampling from various clinical and
geographic settings.
Aims of the study
We collected data from eight international collaborating clinical research sites: (i) Department of
Tondo et al.
anxious, dysthymic, or irritable), (x) lifetime
occurrence of suicidal ideation or acts, (xi) suicide
attempts specically, and (xii) use of illicit drugs
or abuse of alcohol at any time.
The following factors were not included as they
did not dierentiate between the diagnostic groups:
family history of any psychiatric disorder, family
history rate (number of aected/total number of
rst-degree family members), number of siblings,
type of rst-lifetime illness episode, co-occurring
psychiatric or medical illnesses, consumption of
alcohol (without abuse) or caeine, smoking,
body-mass index, hospitalizations/year, and use of
psychotherapy.
These preliminary ndings resembled those
reported previously in similar comparisons (9, 19)
and were reviewed critically with senior colleagues
in the collaborating sites to assess their general
applicability across sites. All collaborating sites
provided data on all 12 factors tested.
Data analyses
We compared averages of each of the 12 stated factors among the three diagnostic groups of interest
(BDp vs. SA, SA vs. SZ; BDp vs. SZ). Preliminary,
pairwise comparisons used contingency tables (v2),
or MannWhitney U-tests (z-score) owing to nonnormal distributions of continuous measures.
Averages are presented as means standard deviation or with 95% condence interval (CI). Dierences between diagnostic pairs were compared: (i)
as averages of factor-prevalences; (ii) with random-eects meta-analysis based on numbers of
subjects with vs. without factors present in diagnostic pairs; and (iii) with multivariate logistic
regression modeling, separately for sociodemographic and clinical characteristics, with each diagnostic pair as the outcome measure. We also
considered measures of variance for each factor
between diagnostic groups, based on coecients of
variation (SD/mean) for continuous measures, and
ratio of condence interval [(upperlower)] to percentage for prevalences. Statistical signicance
required two-tailed P < 0.05. Statistical methods
used commercial software (Statview.5; SAS Institute, Cary, NC, USA to construct data spreadsheets; Stata.12; StataCorp, College Station, TX,
USA for analyses).
Sites
Barcelona
Boston
Buenos Aires
Cagliari
Lugano
Rome-Centro Bini
Rome-SantAndrea
Rome- Santa Lucia
Totals (%)
Bipolar
psychotic
Schizoaffective
Schizophrenia
Total/site
483
244
64
254
79
37
202
72
1435 (63.2)
83
76
42
59
55
16
15
25
371 (16.4)
0
50
11
122
76
27
60
117
463 (20.4)
566
370
117
435
210
80
277
214
2269 (100)
Results
Subjects
Diagnostic comparisons
Table 2. Characteristics of patients diagnosed with bipolar disorder (BD) with psychotic features (BDp) vs. schizoaffective disorder (SA) vs. schizophrenia (SZ)
v2 or z-score (P-value)
Measure
Characteristic
Sociodemographic
Women [n (%)]
Current age (mean SD)
Education high school (%)
Employed (%)
Ever married (%)
Clinical
Family history of BD (%)
Cyclo or hyperthymic (%)
Onset age (mean SD)
Onset stressors (%)
Substance abuse (%)
Suicidal (%)
Acts or ideation
Acts
BDp (n = 1435)
SA (n = 371)
SZ (n = 463)
BDp vs. SA
BDp vs. SZ
SA vs. SZ
765 (53.3)
44.1 15.2
64.4
59.1
50.0
175 (47.2)
40.9 13.9
64.0
46.4
34.5
157 (33.9)
36.6 12.2
58.7
36.2
15.8
4.45 (0.03)
3.46 (0.0005)
0.01 (0.90)
19.4 (<0.0001)
28.3 (<0.0001)
52.8 (<0.0001)
9.04 (<0.0001)
4.42 (0.03)
73.2 (<0.0001)
168 (<0.0001)
15.1 (0.0001)
3.96 (<0.0001)
2.31 (0.13)
8.66 (0.003)
39.5 (<0.0001)
31.1
45.6
27.5 11.0
65.7
41.1
24.2
31.8
25.9 9.71
54.6
32.9
14.9
24.3
24.0 9.67
57.1
31.3
11.5 (0.0007)
22.4 (<0.0001)
2.31 (0.02)
15.4 (0.0001)
8.36 (0.004)
46.3 (<0.0001)
66.5 (<0.0001)
5.79 (<0.0001)
11.4 (0.0007)
14.2 (0.0002)
7.20 (0.007)
5.98 (0.01)
2.66 (0.008)
0.44 (0.51)
0.23 (0.63)
58.7
29.0
57.5
26.5
35.6
16.1
0.19 (0.66)
0.96 (0.33)
74.6 (<0.0001)
29.9 (<0.0001)
39.4 (<0.0001)
13.1 (0.0003)
Continuous measures (with skewed distributions) are compared by nonparametric MannWhitney U-tests (z-score); proportions are compared with contingency tables (v2).
We used logistic, multivariate modeling to compare sociodemographic and clinical factors separately for the three pairs of diagnostic comparisons
as the outcome measures: (i) BDp vs. SA (Table 3),
(ii) SA vs. SZ (Table 4), and (iii) BDp vs. SZ
(Table 5). For sociodemographic factors, BDp
subjects were signicantly more likely than SA
subjects to be employed or married, but did not
dier by sex distribution, current age, or completion of high school. Among clinical factors, these
diagnostic groups diered only in that BDp subjects more often reported stressors close to illness
onset (Table 3).
SA subjects were more likely than SZ subjects to
have married, be employed, or be female, but were
not more highly educated or older. Clinically, SA
OR
95% CI
v2
P-value
= 1720)
1.65
1.94
1.302.09
1.522.47
17.3
28.5
<0.0001
<0.0001
1.59
1.222.06
11.9
0.0006
Table 4. Significant associations in multivariate comparisons of schizoaffective disorder vs. schizophrenia subjects
Factors
A. Sociodemographic factors (n
Ever married
Employed
Female
B. Clinical factors (n = 340)
Suicidal acts or thoughts
Cyclo/hyperthymia
OR
95% CI
v2
P-value
= 777)
2.48
1.55
1.46
1.743.53
1.152.08
1.081.66
25.3
8.25
5.92
<0.0001
0.004
0.01
2.20
2.03
1.302.73
1.043.96
8.54
4.26
0.004
0.04
Tondo et al.
Table 5. Significant associations in multivariate comparisons of bipolar-psychotic
disorder vs. schizophrenia subjects
Factors
OR
95% CI
v2
P-value
2.815.10
1.863.03
1.292.15
1.011.03
57.6
53.0
15.5
9.30
<0.0001
<0.0001
<0.0001
0.002
2.127.21
1.444.98
1.313.41
1.001.05
19.0
9.66
9.32
4.35
<0.0001
0.002
0.002
0.04
intake. They also were more likely to have cyclothymic or hyperthymic traits, abuse substances,
report suicidal ideation or acts, and be somewhat
older at illness onset, but did not dier by family
history, stressors at onset, or suicidal acts
(Table 5).
Graphical comparisons of characteristics among diagnostic groups
Diagnostic comparisons
Sociodemographic factors
Clinical factors
%-Women
Family history of BD
Age
Stressors at onset
Onset
Cyclo-hyperthymic
High school
Substance abuse
Ever married
Suicidal act/ideation
Employed
Suicidal act
10
20
30
40
50
60
70
80
90 100
10 20 30 40 50 60 70 80 90 100 110
Schizoaffective
Schizophrenia
Fig. 1. Comparison of 12 features in subjects diagnosed with DSM-IV-TR: (a) bipolar disorder with psychotic features (n = 1435;
gray bars), (b) schizoaective disorder (n = 371; striped bars), or (c) schizophrenia (n = 463; black bars). Values of sociodemographic
(n = 6) and clinical (n = 6) factors are percentages of mean values for psychotic bipolar disorder subjects as the reference group
(100%). Note that for all measures (except educational level), values for schizoaective disorder are intermediate between those
found with psychotic bipolar disorder and schizophrenia.
SZ subjects (Table 4: Fig. 1). It follows that contrasts between BDp and SZ subjects were even
greater; they involved 8 of 12 factors: BDp subjects
were more likely to have been married or be
employed, female, currently older, to have cyclothymic or hyperthymic traits, to abuse drugs or
alcohol, and to report suicidal ideation or acts, as
well as starting at a somewhat older age (Table 5).
Such strong BDp vs. SZ contrasts were expected
and tend to support the validity of the methods
employed. Being employed and ever married differed most between BDp and both other groups as
well as between SA and SZ and may reect the
youngest age at illness onset in SZ.
The study ndings also support the expectation
that SA subjects would be intermediate between
BDp and SZ subjects, and they were so in almost
all (11/12) of the characteristics considered
(Table 2; Fig. 1). The present analyses of the prevalence of factors between diagnoses did not nd
that SA was signicantly more similar to either
BDp or to SZ. This outcome extends generally
concordant previous ndings based on smaller
samples that included the three diagnostic types (9,
10, 14, 15, 23). Nevertheless, the ndings leave
open basic theoretical questions that have been
Tondo et al.
emphasis on disorders (rather than quantitative
gradations of particular features), and its strong
reliance on the dyadic Kraepelinian model distinguishing major aective-episodic disorders and
essentially non-aective-chronic disorders, despite
the existence of many cases that are not readily categorized as either (13, 15).
The present ndings do not contribute clearly to
diagnostic models conceiving of SA as closer to
either SZ or BD. However, the disorders diered
signicantly in many factors (Table 2), possibly
suggesting that SA represents a third disorder.
Most of the factors considered can easily be
assessed at initial clinical presentation, and their
consideration may help in diagnosis, treatmentselection, and prognosis. In general, SA remains
relatively little studied (16), particularly with
respect to its longitudinal course and outcomes, its
responses to specic treatments, and its biology
(34, 35). This deciency may reect a lack of consensus or a secure research basis for criteria with
which to dene and diagnose SA in currently standard international diagnostic systems, especially
without longitudinal assessment (19, 36, 37). Of
note, a longitudinal knowledge of patients may be
even more important in applying DSM-5 diagnostic criteria for SA than earlier criteria (36). Moreover, therapeutic trials that have been reported
often involve mixtures of subjects diagnosed with
SA and SZ as if they were very similar (38), and
they often involve antipsychotic drugs rather than
mood-altering or mood-stabilizing treatments, or
selected combinations of treatment methods (39,
40). Needed are treatment trials of SA subjects
considered separately from other types of subjects,
including trials of mood-stabilizing agents such as
lithium and selected anticonvulsants, as well as antipsychotics, with comparisons of monotherapies
with specic combinations, adjunctive psychosocial interventions, and specic consideration of
eects of treatments on the high suicidal risks associated with the disorder (41).
Limitations of this study include moderate and
unmatched numbers of subjects from specic sites,
as well as special interests of the collaborating
sites, most of which study patients with BD more
than with SZ. These characteristics of samples
may limit generalizability of the ndings, despite
the large aggregate sample from geographically
and culturally diverse sites. Additional hypothetical limitations include potential variance across
sites in the way DSM-IV diagnostic criteria were
ascertained, as well as the limited range of factors
considered. However, the signicant ndings from
several dierent sites is also a strength of this
study. Finally, neuropsychological assessment was
8
not included in this project, despite reportedly differences in cognitive functioning across these conditions (42).
In conclusion, the present ndings add to the
growing impression that BDp, SA, and SZ, at least
as diagnosed by DSM-IV criteria, diered signicantly in most of the 12 sociodemographic and
clinical characteristics considered, with a ranking
of measures consistent with better functioning
(notably including marital and employment status)
as: BDp > SA > SZ, and of onset age in the opposite direction (youngest in SZ). The ndings also
place SA approximately mid-way between BDp
and SZ (34). In addition, variance of factor measurements was not greater in SA subjects, as might
be expected if it is a more heterogeneous condition.
Nevertheless, the old and persistent question
remains of whether and how to divide major psychotic disorders nosologically. The ndings also
underscore the need for further epidemiological,
clinical, therapeutic, and biological studies of SA,
especially in comparison with BDp and SZ.
Acknowledgement
Hari-Mandir K. Khalsa, MA, provided valuable assistance
with data management.
Declaration of interests
Ross Baldessarini has received grant support by the Bruce J.
Anderson Foundation and the McLean Private Donors
Research Fund, as well as serving as a paid consultant to Sunovion Pharmaceuticals and teaching in CME programmes for
Harvard Medical School and New England Educational Institute. Paolo Girardi has received grant support or honoraria
from Eli Lilly, Janssen, and Springer Healthcare Corporations
and participated in Advisory Boards for Eli Lilly, Otsuka, Pzer, Schering, and Springer Corporations. Andrea Murru has
received grant support from Bristol-Myers Squibb and speakers honoraria from ADAMED, AstraZeneca, Janssen, Lundbeck and Otsuka Corporations. Isabella Pacchiarotti has
received honoraria or consulting fees from ADAMED, Janssen and Lundbeck Corporations. Gianfranco Spalletta has
received grant support from the Italian Ministry of Health
(RC11-12-13-14/A). Mauricio Tohen has received honoraria
from, or consulted for Abbott, Alkermes, AstraZeneca, Bristol-Myers Squibb, Elan, Forest, Geodon, GlaxoSmithKline,
Johnson & Johnson, Lilly, Lundbeck, Merck, Otsuka, Pamlab,
Richter, Roche, Sunovion, Teva, Wiley, and Wyeth Corporations. Leonardo Tondo has received grant support from the
Aretus Association of Rome and from private donors. Gustavo V
azquez has served as a consultant or speaker for AstraZeneca, Ferrer, Gador, GlaxoSmithKline, Ivax-Teva, Eli Lilly,
Lundbeck, Pzer, Rao, Servier and Novartis Pharmaceuticals. Eduard Vieta has received honoraria from, or consulted
for, Astra Zeneca Bristol-Myers Squibb, Elan, Ferrer, Forest,
Gedeon Richter, GlaxoSmithKline, Janssen, Lilly, Lundbeck,
Otsuka, Roche, Sunovion, and Takeda and has received grant
support from Fondos para la Investigaci
on Sanitaria (FIS),
Generalitat de Catalunya (SGR398), and Instituto de Investi-
Diagnostic comparisons
gaci
on Carlos III (PI12/00912). Other authors and all immediate family members have no nancial relationships that might
appear to present conict of interests.
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