Acta Psychiatr Scand 2015: 110

All rights reserved

DOI: 10.1111/acps.12447

2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
ACTA PSYCHIATRICA SCANDINAVICA

Comparison of psychotic bipolar disorder,

schizoaective disorder, and schizophrenia:
an international, multisite study
Tondo L, V

azquez GH, Baethge C, Baronessa C, Bolzani L,
Koukopoulos A, Mazzarini L, Murru A, Pacchiarotti I, Pinna M,
Salvatore P, Sani G, Selle V, Spalletta G, Girardi P, Tohen M, Vieta E,
Baldessarini RJ. Comparison of psychotic bipolar disorder,
schizoaective disorder, and schizophrenia: an international, multisite
study.
Objective: Nosological distinctions among schizoaective disorder
(SA), bipolar I disorder with psychotic features (BDp), and
schizophrenia (SZ) remain unresolved.
Method: We compared 2269 subjects with psychotic features in DSMIV-TR diagnoses (1435 BDp, 463 SZ, 371 SA) from 8 collaborating
international sites, by 12 sociodemographic and clinical measures, all
between diagnostic pairs.
Results: In bivariate comparisons, SA was consistently intermediate
between BDp and SZ for 11/12 features (except onset stressors), and SZ
vs. BDp diered in all 12 factors. SA diered from both BDp and SZ in
9/12 factors: SA and BDp were similar in education and suicidal
ideation or acts; SA and SZ were similar in education, onset stressors,
and substance abuse. Meta-analytic comparisons of diagnostic pairs for
10 categorical factors indicated similar dierences of SA from both SZ
and BDp. Multivariate modeling indicated signicantly independent
dierences between BDp and SZ (8 factors), SA vs. SZ (5), and BDp vs.
SA (3). Measurement variance was similar for all diagnoses.
Conclusion: SA was consistently intermediate between BDp and SZ.
The three diagnostic groups ranked: BDp > SA > SZ related to lesser
morbidity or disability. The ndings are not consistent with a dyadic
Kraepelinian categorization, although the considerable overlap among
the three DSM-IV diagnostic groups indicates uncertain boundaries if
they represent distinct disorders.

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

Department of Psychiatry, Harvard Medical School,

International Consortium for Bipolar & Psychotic
Disorder Research, Boston, MA, USA, 2Lucio Bini Mood
Disorder Center, Cagliari, Italy, 3Department of
Neuroscience, Palermo University, Buenos Aires,
Argentina, 4Department of Psychiatry, University of Koln,
Koln, Germany, 5Viarnetto Psychiatric Clinic, Lugano,
Switzerland, 6NeSMOS Department, SantAndrea
Medical Center, University of Rome (Sapienza), Rome,
7
Lucio Bini Mood Disorder Center, Rome, Italy, 8Bipolar
Disorders Unit, Institute of Neuroscience, Hospital
Clnic, University of Barcelona, IDIBAPS, CIBERSAM,
Barcelona, Spain, 9Section of Psychiatry, Department of
Neuroscience, University of Parma, Parma,
10
Neuropsychiatry Laboratory, Department of Clinical
and Behavioral Neurology, IRCCS Santa Lucia
Foundation, Rome, Italy, 11Beth K. and Stuart C.
Yudofsky Division of Neuropsychiatry, Menninger
Department of Psychiatry and Behavioral Sciences,
Baylor College of Medicine, Houston, TX, and
12
Department of Psychiatry, University of New Mexico,
Albuquerque, NM, USA
Key words: bipolar disorder; comparisons; psychosis;
schizoaffective; schizophrenia
Leonardo Tondo, Mailman Research Center, McLean
Hospital, 115 Mill Street, Belmont, MA 02478-9106,
USA. E-mail: ltondo@aol.com

Accepted for publication April 30, 2015

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

Potential variance in application of diagnostic criteria across sites.

Possible inuence on diagnoses because of special interests at collaborating sites, most of which study
bipolar disorder more than patients with schizophrenia.

Generalizability of ndings to other settings may be limited despite the large aggregate sample from
geographically and culturally diverse sites.

Many psychological or biological assessments of potential interest were not included.

Perhaps it is also possible. . .to tackle the diculties
which still prevent us from distinguishing reliably
between manic-depressive insanity and dementia prcox. No experienced psychiatrists will deny that there is
an alarmingly large number of cases in which it seems
impossible, in spite of the most careful observation, to
make a rm diagnosis. Emil Kraepelin (1920) (1)

Introduction

The diagnostic categorization, clinical features,

optimal treatment, course, and outcome of major
psychiatric disorders with psychotic features
remain unresolved despite more than a century of
experience and investigations. Since the work of
Kraepelin in the late 1890s, such illnesses usually
have been divided into those marked by prominent
aective and behavioural features, a periodic
course, and relatively favorable outcome vs. those
considered largely non-aective and typically
chronic disorders of reasoning with impaired functioning. In his late writings, Kraepelin acknowledged that a large proportion, possibly a majority,
of patients with psychotic disorder he had evaluated did not t neatly into either of his manicdepressive or dementia prcox (schizophrenia) categories (13). The Wernicke-Kleist-Leonhard
2

school of German psychiatry also emphasized that

many cases of psychotic illnesses did not correspond
with Kraepelins categories, distinguished subtypes
of schizophrenia, and described a novel group of
cycloid psychoses with relatively favorable prognosis (46). In recent decades, cases that appear
to share features of both of Kraepelins major
groups have been considered either to represent
particular forms of schizophrenia or manic-depressive disorder, or to represent separate, intermediate
conditions often labeled schizoaective.
Since its proposal as a clinical diagnosis early in
the 20th century, schizoaective disorder (SA) has
been considered in various ways: (i) as a residual
category for those not fullling criteria for schizophrenia (SZ) or bipolar manic-depressive disorder,
especially with psychotic features (BDp); (ii) an
intermediate entity on a continuum of psychotic
disorders, arising from the 19th-century unitary
psychosis (Einheitpsychose) concept espoused by
Ghislain, Griesinger, and others (7, 8); (iii) a relatively moderate form of SZ; (iv) a severe form of
BD; or (v) an independent clinical entity (911).
The term schizoaective disorder originally was
applied by Kasanin in the United States in the
1930s to relatively acute psychotic conditions with
prominent aective features (12). In recent decades, characterizations of a SA group have come

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 hypothesized that the three diagnostic groups

would dier signicantly from one another in one or
more of several tested features and that most measures in schizoaective disorder would be intermediate between those associated with bipolar I disorder
with psychotic features and schizophrenia.
Material and methods

We collected data from eight international collaborating clinical research sites: (i) Department of

Neuroscience, Palermo University, Buenos Aires,

Argentina; (ii) Department of Psychiatry, Hospital
Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain; (iii) IRCSS Santa
Lucia Foundation Neuropsychiatry Laboratory,
Department of Clinical and Behavioral Neurology,
Rome, Italy; (iv) Lucio Bini Mood Disorder Center, Cagliari, Italy; (v) Lucio Bini Mood Disorder
Center, Rome, Italy; (vi) McLean Hospital, Belmont, Massachusetts; (vii) NeSMOS Department,
SantAndrea Medical Center, Sapienza University
of Rome; and (viii) Viarnetto Psychiatric Clinic,
Lugano, Switzerland.
Information assembled included detailed clinical
characteristics of patients diagnosed by consensus
of authors at each study site with bipolar type I disorder with psychotic features (BDp), schizoaective disorder (SA), or schizophrenia (SZ), who
consistently met the corresponding DSM-IV-TR
diagnostic criteria during at least 12 months of
clinical observation. Data collection was based on
reviewing clinical records as well as on interviews
at intervals of 112 weeks, as required clinically.
Data were obtained from detailed, semistructured
clinical records and considered all patients with
psychotic features at any time. This sampling process at the 8 international sites yielded a total of
2269 subjects meeting DSM-IV diagnostic criteria
for the three categories of interest, representing dissimilar cultures and geographic regions (Europe,
North America, South America), and included currently hospitalized (30.9%), initially hospitalized
(16.3%), and ambulatory cases (52.8%).
In order to identify measures likely to be of
interest, pilot testing was performed in the 435
patients in treatment at Lucio Bini Mood Disorders Center in Cagliari (Sardinia) who met DSMIV diagnostic criteria for the three disorders of
interest. The following sociodemographic and
clinical characteristics were found to distinguish
the three diagnostic groups, based on statistical
signicance in between-diagnosis comparisons, as
is detailed below for the entire study cohort. Sociodemographic features were as follows: (i) sex, (ii)
current age, (iii) educational level (at least completing high school), (iv) employment at intake
(including students, homemakers, currently retired
persons, and part-time workers), and (v) marital
status (ever married or in a stable, long-term
domestic relationship, or unmarried at intake).
Clinical characteristics were as follows: (vi) family
history of probable BD, (vii) approximate age at
onset of the illness, (viii) stressors identied as
occurring within 90 days before a rst-lifetime
episode of illness, (ix) clinically categorized temperament type (cyclothymic or hyperthymic vs.
3

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).

with BDp, 463 (20.4%) SZ, and 371 (16.4%) with

SA. Seven of the 8 sites provided cases from all three
diagnostic groups (Table 1). Overall, 51.6% of the
subjects were men, and current age averaged 42.1
(95% CI: 41.542.7) years.
Comparisons of diagnostic pairs

The magnitude of measures of sociodemographic

and clinical factors across diagnostic groups
ranked BDp > SA > SZ for 11/12 factors (except
that onset stressors ranked: BDp > SZ > SA). SA
and BDp were similar in education and suicidal
ideation or acts; SA and SZ were similar in education, onset stressors, and substance abuse
(Table 2). In general, and unsurprisingly, all 12
factors were signicantly dierent between BDp
and SZ (Table 2).
We tested the possibility that measures in SA
subjects might be more heterogeneous than in
either BDp or SZ. However, variances of the continuous measures (onset and current ages) were
very similar across diagnostic groups. For onset
age, the coecients of variation (SD/mean) were
as follows: SZ (0.403), BDp (0.402), and SA
(0.376); for current age, these coecients were as
follows: BDp (0.345), SA (0.340), and SZ (0.333),
indicating similar variance of these continuous
measures across diagnostic groups. For the 10
percentage measures, we computed the ratio of
95% condence intervals (high minus low) to rates
as an estimate of variance. These values averaged
[mean (CI)]: for BDp [10.7 (8.6912.7)] < SA [25.8
(20.631.0)] SZ [29.9 (22.237.6)], again indicating that measurement variance was not largest in
SA subjects.

Table 1. Distribution of study subjects by collaborating site

Cases (n)

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

The total of 2269 subjects meeting DSM-IV-TR

diagnostic criteria included: 1435 (63.2%) diagnosed
4

Cases from Barcelona are from a mood disorders programme.

Cases from Boston are from an initially hospitalized, first-episode sample.
Cases from Lugano are hospitalized.
Cases from Rome-SantAndrea are either hospitalized or out-patients.
Cases from other sites are out-patients.

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 compared ndings for SA vs. BDp subjects

and also for SA vs. SZ subjects to further evaluate
the relative similarities of the SA subjects to the
other two diagnostic groups. Random-eects
meta-analyses compared rate ratios (RR) pooled
across the 10 categorical factors for pairs of
diagnoses, based on presence vs. absence of each
factor. The resulting pooled relative rates (RR)
ranked: BDp vs. SZ (RR = 1.59, CI: 1.242.05;
z = 3.65, P < 0.0001) SA vs. SZ (RR = 1.28, CI:
1.061.54; z = 2.56, P = 0.01) BDp vs. SA
disorder (RR = 1.23, CI: 1.081.41; z = 3.10,
P = 0.002). That is, all three paired comparisons
indicated signicant dierences between each pair
of diagnoses, with similar dierences of SA from
either SZ or BDp, and the largest dierence, as
expected, was between BDp and SZ.
Multivariate modeling

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

Table 3. Significant associations in multivariate comparisons of bipolar-psychotic

vs. schizoaffective disorder subjects
Factors
A. Sociodemographic factors (n
Employed
Ever married
B. Clinical factors (n = 1374)
First-episode stressors

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

Based on separate logistic regression models (A and B).

Not significantly associated with bipolar disorder were: A. sex, education, and age;
B. family history of bipolar disorder, cyclo/hyperthymic temperament, onset age,
substance abuse, and suicidal ideation or acts.

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

Based on separate logistic regression models (A and B).

Not significantly associated with schizoaffective disorder were: A. education and
age; B. family history of bipolar disorder, onset age, stressors at first episode, suicidal acts alone, and substance abuse.

subjects were more likely to have had suicidal acts

or thoughts as well as cyclothymic or hyperthymic
traits, but otherwise these groups did not dier signicantly (Table 4).
Subjects diagnosed with BDp also were signicantly more likely than those with SZ to be married, employed, and female, and somewhat older at
5

Tondo et al.
Table 5. Significant associations in multivariate comparisons of bipolar-psychotic
disorder vs. schizophrenia subjects
Factors

OR

A. Sociodemographic factors (n = 1656)

Ever married
3.65
Employed
2.37
Female
1.66
Older current age
1.02
B. Clinical factors (n = 1102)
Cyclo/hyperthymic
3.91
Substance abuse
2.68
Suicidal acts or thoughts
2.11
Older onset age
1.03

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

Based on separate logistic regression models (A and B).

Not significantly associated with bipolar disorder were: A. education; B. family history of bipolar disorder, stressors at onset, and suicidal acts alone.

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

Factors compared among the three diagnoses are

shown graphically by comparison as the
percentage of the value of each measure in BDp
subjects set as 100% (Fig. 1). Eleven of the 12
factors considered ranked numerically as
BDp > SA > SZ; the exception was stressors at
onset).
Discussion

This international collaborative study involved a

large sample of 2269 adult patients diagnosed with
one of three major types of psychotic disorders of
interest: BDp, SA, and SZ, based on DSM-IV-TR
(13) criteria (Table 1). Factors compared between
diagnostic pairs included 12 sociodemographic and
clinical measures, selected from preliminary ndings and based on factors considered in previous,
comparable studies. Earlier studies involved BD
subjects who were not necessarily psychotic (9, 10),
and only one sample (20) was larger than ours and
found dierences only in the presence of medical
illnesses (20, 21).
Prevalence of sociodemographic factors (educational and occupational functioning, being married
or in a stable, long-term relationship; clinical: older
onset age) consistently ranked BDp > SA > SZ
(Table 2; Fig. 1), indicating a more favorable educational, occupational, relational, and social accomplishments in persons with BDp compared with
6

other diagnoses. On the other hand, unfavorable

clinical factors (family history of BD, substance
abuse, and suicidal acts) also followed the same
diagnostic ranking (Table 2; Fig. 1). The rate of
suicidal ideation or acts, or suicide attempts specically, did not dier signicantly between BDp and
SA subjects, but both suicidal measures were least
prevalent among SZ subjects. Identication of stressors at illness onset also did not dier between SA
and SZ subjects, and stressors were identied more
often among BDp cases. Consideration of heterogeneity of the measures indicated that variance was
consistently greatest in SZ subjects, least in BDp,
and intermediate in SA. The lack of disproportionate heterogeneity of measures in SA accords with a
recent meta-analysis also nding that patients with
SA did not show more heterogeneity than samples
of patients diagnosed with BD (not all psychotic) or
SZ (22).
Finding family history of probable BD in SZ
and SA subjects (co-aggregation) may seem paradoxical, but has been described previously, and
familial risks of specic psychiatric disorders in
relation to proband diagnoses are likely to vary
quantitatively rather than qualitatively (2224).
That stressors at rst episodes were most prevalent, and onset age oldest among BDp subjects
seem consistent with proposals that the timing of
onset of BD may be relatively stress-sensitive (25)
and may suggest greater environmental sensitivity
in patients with BDp compared with other patients
with psychotic disorder. Moreover, being older at
intake (current age) probably indicates that
patients with BDp sought or were encouraged to
accept clinical help later than subjects diagnosed
with SA or SZ, possibly as a function of relatively
older onset age or less severe or function-impairing
initial episodes. Also, as expected, cyclothymic or
hyperthymic temperaments were signicantly more
likely to be identied than other types in BDp
than in SA or SZ. In addition, substance abuse
was most prevalent in BDp, although its betweendiagnosis dierences were small (Table 2; Fig. 1).
In the present multivariate logistic modeling,
several factors were found to be independently and
signicantly dierent between particular diagnostic
pairs. First, BDp and SA subjects diered in 3 of
12 factors considered: having been married or
employed, and onset associated with identied
stressors were found at higher rates in BDp subjects (Table 3; Fig. 1). SA and SZ subjects diered
signicantly and independently in 5 of the same 12
factors: having been married or employed and
being female, having suicidal acts or thoughts, and
a cyclothymic or hyperthymic temperament all
were signicantly more prevalent among SA than

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

Proportion compared to bipolar cases (%)

Bipolar-psychotic

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

considered for more than a century. Notably, it

remains uncertain whether the major psychotic
diagnostic groups represent three distinct disorders, phenotypically similar clusters averaged
among many potentially separate entities, or a
spectrum of manifestations within a single disorder
(3, 5, 7, 8, 11, 1416). Additional nosological challenges arise in considering how to characterize
brief psychotic disorders from the lifelong, recurring or chronic illnesses considered here (19). It is
possible that advances in brain-structural or functional, molecular, and genetic comparisons of the
diagnostic groups of interest may contribute to
resolving such fundamental diagnostic dilemmas,
although such eorts currently remain preliminary
and tentative (2633). This study adds to the
research on psychotic disorders conrming an
approximately equidistant nosological position of
SA disorder from BDp and SZ, generally, with
greater severity than BDp and less than SZ. This
categorical placement does not seem consistent
with the recent DSM-5 inclusion of SA among
schizophrenia-like disorders. A nal observation is
that reliance on contemporary diagnostic categorization may, itself, introduce an element of bias or
circularity, arising from both its categorical
7

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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