Research

Original Investigation

Boundaries of Schizoaffective Disorder

Revisiting Kraepelin
Roman Kotov, PhD; Shirley H. Leong, PhD; Ramin Mojtabai, MD, PhD, MPH; Ann C. Eckardt Erlanger, PsyD;
Laura J. Fochtmann, MD; Eduardo Constantino, MD; Gabrielle A. Carlson, MD; Evelyn J. Bromet, PhD

Editorial
IMPORTANCE Established nosology identifies schizoaffective disorder as a distinct category Supplemental content at
with boundaries separating it from mood disorders with psychosis and from schizophrenia. jamapsychiatry.com
Alternative models argue for a single boundary distinguishing mood disorders with psychosis
from schizophrenia (kraepelinian dichotomy) or a continuous spectrum from affective to
nonaffective psychosis.

OBJECTIVE To identify natural boundaries within psychotic disorders by evaluating

associations between symptom course and long-term outcome.

DESIGN, SETTING, AND PARTICIPANTS The Suffolk County Mental Health Project cohort
consists of first-admission patients with psychosis recruited from all inpatient units of Suffolk
County, New York (72% response rate). In an inception cohort design, participants were
monitored closely for 4 years after admission, and their symptom course was charted for 526
individuals; 10-year outcome was obtained for 413.

MAIN OUTCOMES AND MEASURES Global Assessment of Functioning (GAF) and other
consensus ratings of study psychiatrists.

RESULTS We used nonlinear modeling (locally weighted scatterplot smoothing and spline
regression) to examine links between 4-year symptom variables (ratio of nonaffective
psychosis to mood disturbance, duration of mania/hypomania, depression, and psychosis)
and 10-year outcomes. Nonaffective psychosis ratio exhibited a sharp discontinuity10 days
or more of psychosis outside mood episodes predicted an 11-point decrement in
GAFconsistent with the kraepelinian dichotomy. Duration of mania/hypomania showed 2
discontinuities demarcating 3 groups: mania absent, episodic mania, and chronic mania
(manic/hypomanic >1 year). The episodic group had a better outcome compared with the
mania absent and chronic mania groups (12-point and 8-point difference on GAF). Duration of
depression and psychosis had linear associations with worse outcome.

CONCLUSIONS AND RELEVANCE Our data support the kraepelinian dichotomy, although the
study requires replication. A boundary between schizoaffective disorder and schizophrenia
was not observed, which casts further doubt on schizoaffective diagnosis. Co-occurring
schizophrenia and mood disorder may be better coded as separate diagnoses, an approach Author Affiliations: Department of
that could simplify diagnosis, improve its reliability, and align it with the natural taxonomy. Psychiatry and Behavioral Science,
Stony Brook University, Stony Brook,
New York (Kotov, Fochtmann,
Constantino, Carlson, Bromet);
Department of Psychiatry, University
of Pennsylvania, Philadelphia
(Leong); Department of Mental
Health, Johns Hopkins Bloomberg
School of Public Health, Baltimore,
Maryland (Mojtabai); Department of
Cardiology and Comprehensive Care,
New York University, New York
(Erlanger).
Corresponding Author: Roman
Kotov, PhD, Department of
Psychiatry and Behavioral Science,
Putnam Hall-South Campus, Stony
JAMA Psychiatry. doi:10.1001/jamapsychiatry.2013.2350 Brook University, Stony Brook, NY
Published online October 2, 2013. 11794 (roman.kotov@stonybrook.edu).

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 Research Original Investigation
T
he delineation of schizophrenia (dementia praecox) and
psychotic mood disorders (manic-depressive insanity)
as 2 distinct entities was one of Emil Kraepelins semi-
nal contributions to nosology.1 More than 100 years later, this
kraepelinian dichotomy remains highly influential.2 How-
ever, some patients exhibit features of both schizophrenia and
psychotic mood disorders, which led Kasanin3 to propose a new
category labeled schizoaffective disorder. Conceptualization of
this condition evolved across editions of the DSM from a sub-
type of schizophrenia to a distinct disorder. DSM-IV4 defines
it as (A) co-occurrence of schizophrenia symptoms and mood
episodes, (B) psychosis present for at least 2 weeks in the ab-
sence of mood symptoms, and (C) mood episodes present for
a substantial portion of illness duration. Thus, DSM-IV elabo-
rates on the kraepelinian dichotomy by adding an intermedi-
ate condition, with criterion B defining its boundary with psy-
chotic mood disorder and criterion C with schizophrenia. The
key to classifying these disorders is the ratio of nonaffective
psychosis to mood disturbance: in psychotic mood disorder,
nonaffective psychosis is absent; in schizoaffective disorder,
both nonaffective psychosis and mood episodes are promi-
nent; and in schizophrenia, nonaffective psychosis predomi-
nates. However, some have argued that these boundaries are
artificial and that psychotic disorders fall along a continuous
spectrum that ranges from psychotic mood disorder to
schizophrenia.5,6
These conflicting accounts inspired a substantial body of
literature that evaluated the validity of schizoaffective disor-
der using several basic approaches. Investigations of phenom-
enology found support for the continuum model,7 the krae-
pelinian 2-disorders model,8,9 and the DSM-IV 3-disorders
model.10 Studies of neurobiological and cognitive function-
ing, as well as family and genetic research, reported evidence
favoring the continuum7,11 and 3-disorders12-14 models. Lon-
gitudinal studies of illness course produced the most support
for the continuum15,16 and 2-disorders8,17-20 models. Thus, to
date, the literature is too conflicting to offer firm recommen-
dations for nosology. Some of these inconsistencies likely re-
sult from changes in schizoaffective diagnosis, which was de-
fined more broadly by earlier diagnostic manuals.
Among diagnostic validators, illness course is of particu-
lar interest. Indeed, it was most central to Kraepelins work be-
cause he sought to develop diagnoses that would be prognos-
tic of future symptoms and functioning (ie, global outcome).2
Unfortunately, existing longitudinal studies were not de-
signed to answer questions about the natural organization of
psychotic disorders. They typically compared outcomes among
diagnostic groups: schizophrenia, schizoaffective disorder, and
psychotic mood disorder, but such analyses cannot distin-
guish gradual differences (ie, a continuum) from qualitative
changes (ie, natural boundaries). Indeed, in many studies15,16
outcome of schizoaffective disorder fell between that of schizo-
phrenia and psychotic mood disorder, which is consistent with
both the continuum and 3-disorders models.
Kendell and Brockington21 proposed a solution to this prob-
lem. They examined associations between the spectrum rang-
ing from typical psychotic mood disorder to typical schizo-
phrenia and continuous outcome measures. Their hypothesis
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Boundaries of Schizoaffective Disorder
was that a natural boundary would manifest as a significant
drop in the outcome at some point along the spectrum, whereas
a continuum would result in a linear decline. Kendell and
Brockington found no evidence of a boundary, but their study
was underpowered and analyses were limited to visual inspec-
tion of graphs.22 The latter shortcoming might explain why this
technique has not been widely adopted. More recent devel-
opments in statistical methods23 make it possible to test such
data for nonlinearity rigorously.
The aim of the present study was to test for the existence
of natural boundaries in psychotic disorders using modern sta-
tistical methods. We analyzed detailed symptom course data
from an epidemiologic cohort of inpatients with psychosis
monitored prospectively for 10 years after their first hospital-
ization. In particular, we examined links between nonaffec-
tive psychosis ratio during the first 4 years of the study and
outcomes at year 10. The continuum model predicts a linear
association, the kraepelinian model predicts a single bound-
ary between psychotic mood disorder and the schizophrenia
spectrum, and the DSM-IV model predicts 2 boundaries, one
between psychotic mood disorder and schizoaffective disor-
der and another between schizoaffective disorder and schizo-
phrenia (Supplement [eFigure 1]). In the latter 2 models, dif-
ferences are expected between groups (eg, low nonaffective
psychosis and high nonaffective psychosis), but no associa-
tion is predicted between nonaffective psychosis and out-
come within groups. We constructed statistical models to test
these hypotheses. We also used this method to explore natu-
ral boundaries within depression and mania.
Methods
Participants
Data for this study came from the Suffolk County Mental Health
P rojec t, an epidemiologic study of first-admission
psychosis.24-26 Patients were recruited from the 12 psychiat-
ric inpatient units of Suffolk County, New York, between Oc-
tober 1989 and December 1995. Inclusion criteria were first ad-
mission, either current or within 6 months; clinical evidence
of psychosis; age 15 to 60 years; IQ higher than 70; profi-
ciency with English; and no apparent general medical etiol-
ogy. The study was approved annually by the institutional re-
view boards of Stony Brook University and the participating
hospitals. Treating physicians determined participants ca-
pacity to provide consent. Written consent was obtained from
adults and from parents of patients younger than 18 years.
We initially interviewed 675 participants (72% of refer-
rals); 628 of them met the eligibility criteria. By the 4-year point,
10 participants had died, 29 were untraceable, 41 refused fur-
ther participation, and 22 provided insufficient information
about symptom course; the remaining 526 participants (83.8%)
constituted the course sample. Of them, by the 10-year assess-
ment, 27 had died, 28 were untraceable, 41 refused further par-
ticipation, and 17 provided insufficient outcome informa-
tion; the remaining 413 participants (78.5%) compose the
outcome sample. These samples were very similar to each other
and to the total cohort on the study variables (Table 1). The only
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 Boundaries of Schizoaffective Disorder Original Investigation Research

Table 1. Demographic and Clinical Characteristics of the Sample

No. (%)a
Total
Cohort Course Sample Outcomes Sample
Characteristic (N = 628) (n = 526) (n = 413)
Age at baseline, mean (SD), y 29.7 (9.7) 29.2 (9.5) 29.1 (9.5)
Male sex 365 (58.1) 299 (56.8) 231 (55.9)
White race 470 (74.8) 400 (76.0) 313 (75.8)
SES of family of origin: blue collar 284 (45.2) 236 (44.9) 199 (48.2)
DSM-IV diagnosis at year 2
Schizophrenia/schizophreniform 199 (33.8) 184 (35.1) 145 (35.1)
Schizoaffective 30 (5.1) 26 (5.0) 21 (5.1)
Abbreviations: GAF, Global
Bipolar with psychosis 148 (25.1) 135 (25.8) 112 (27.1)
Assessment of Functioning; GAF-F,
MDD with psychosis 104 (17.7) 91 (17.4) 68 (16.5) Global Assessment of Functional
Other psychoses 108 (18.3) 88 (16.8) 67 (16.2) Performance; GAS, Global
Assessment of Symptoms;
Symptom course, mean (SD)
MDD, major depressive disorder;
% Psychosisb NA 36.4 (38.4) 37.4 (38.7) NA, not applicable; SADS, Schedule
% Maniab NA 7.5 (18.6) 8.3 (19.9) for Affective Disorders and
Schizophrenia; SES, socioeconomic
% Depressionb NA 24.0 (32.6) 24.5 (32.8)
status.
% Nonaffective psychosis ratioc NA 35.7 (43.4) 34.9 (43.0) a
Percentages may vary because of
Outcome, mean (SD)d missing data.
b
GAF NA NA 54.8 (16.2) Percentage of observed interval
GAF-F NA NA 57.5 (15.9) from baseline to 4-year point.
c
Percentage of illness during interval
GAS NA NA 57.4 (16.5)
from baseline to 4-year point.
Psychosocial functioning (SADS) NA NA 2.4 (1.2) d
Outcome at 10-year point.

significant differences between the course sample and the rest
of the cohort (n = 102) were slightly younger age (P = .008) and
lower prevalence of other psychoses in the sample (P = .044).
The only significant difference between the outcome sample
and the rest of the course sample (n = 113) was the slight over-
representation of patients with low parental socioeconomic sta-
tus in the former (P = 008).
Measures
Face-to-face assessments were conducted by masters level
mental health professionals at baseline, 6-month, 2-year,
4-year, and 10-year follow-up; telephone interviews were per-
formed every 3 months until the 2-year wave and every 6
months until the 4-year wave. Interviewers were blinded to
study diagnoses. Medical records and interviews with signifi-
cant others were also obtained at each major assessment. These
detailed data allowed raters to chart symptom course be-
tween baseline and year 4. At least half of the interval was docu-
mented for everyone in the course sample; 91.7% of them had
at least 3.5 years of follow-up data.
Symptom documentation included start and end dates of
psychotic, depressive, and manic episodes, each rated sepa-
rately and defined according to DSM-IV criteria except for du-
ration, which we did not require. Episodes were scored as
(1) percentage of the observed interval psychotic, (2) percent-
age of patients depressed, and (3) percentage of patients manic
(including hypomania). Of particular interest was the nonaf-
fective psychosis ratio, scored as percentage of illness psy-
chotic and not in mood episode (illness was defined as mood
or psychotic episode), because this ratio defines the diagnos-
tic boundaries of schizoaffective disorder in DSM-IV (espe-
cially criterion C).
Overall outcome is particularly relevant to validation of
psychotic disorders.1,15,17,18 We examined 3 measures target-
ing its different aspects: Global Assessment of Symptoms (GAS)
indicated overall symptom severity in the best month be-
tween the 4-year and 10-year interviews, Global Assessment
of Functional Performance (GAF-F) indicated overall social and
occupational functioning in the best month between 4-year and
10-year interviews, and Global Assessment of Functioning
(GAF) was rated for the best month of the year before the 10-
year interview considering both symptoms and functioning.
Each measure was rated on a 0 to 90 scale (with 10 anchors spe-
cific to that rating) according to the DSM-III-R version of GAF,
which was standard at the start of this study. To ensure that
results were not influenced by format, we also evaluated the
overall rating of psychosocial functioning from the Schedule
for Affective Disorders and Schizophrenia (SADS),27 scored as
1, marked chronic condition; 2, moderate chronic condition;
3, mild chronic condition; and 4, complete return to highest
functioning. These ratings were made by consensus of study
psychiatrists (including L.J.F., E.C., and G.A.C.). Interrater re-
liability of consensus scores could not be assessed, but reli-
ability of the individual raters was excellent, ranging intra-
class r = 0.90-0.94 across outcomes.
Primary DSM-IV diagnosis was formulated at the 2-year
point by consensus of 4 or more psychiatrists (including L.J.F.
and G.A.C.) using all available information, including Struc-
tured Diagnostic Interview for DSM-IV28 with participants,
medical records, and significant others.26 Diagnoses were

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 Research Original Investigation Boundaries of Schizoaffective Disorder

Table 2. Multiple Linear Regression Analyses of 4-Year Course Predicting 10-Year Outcomes

Global Assessment
Psychosocial
Functioning (Overall) Functional Performance Symptoms Functioning
P
Predictor/Outcome B P Value B P Value B P Value B Value
Intercept 65.54 69.05 69.48 3.33
% Psychosis 16.20 0.39 <.001a 14.08 0.35 <.001a 17.17 0.40 <.001a 1.08 0.34 <.001a
a a
% Mania 3.95 0.05 .28 2.07 0.03 .56 1.83 0.02 .61 0.21 0.03 .44
% Depression 6.43 0.13 .02a 9.88 0.21 <.001a 8.30 0.17 .002a 0.77 0.20 <.001a
% Nonaffective psychosis ratio 7.90 0.21 .001a 10.96 0.30 <.001a 10.45 0.27 <.001a 0.89 0.31 <.001a
a
Abbreviations: B, unstandardized regression coefficient; , standardized P < .01 considered significant.
regression coefficient.

grouped into 5 categories: schizophrenia/schizophreniform,
schizoaffective, bipolar with psychosis, depression with psy-
chosis, and other psychoses (eg, psychosis not otherwise speci-
fied and substance-induced psychosis). In assigning schizoaf-
fective disorder diagnosis, psychiatrists interpreted criterion
C (substantial portion) as requiring mood disturbance to be pres-
ent for more than 30% of illness duration.
Demographic characteristics were also considered in analy-
ses. They included age at baseline, sex, race, and socioeco-
nomic status of the head of household.
Statistical Analysis
First, we examined relationships between the 4 symptom
course predictors and 4 outcomes using locally weighted scat-
terplot smoothing (LOESS),29,30 which uses weighted least
squares to fit linear functions within a fixed neighborhood of
each data point. If LOESS indicated nonlinearity of the asso-
ciation, we evaluated its exact form using spline regression.31-33
Spline regression is a piecewise regression that fits polyno-
mial functions onto segments of the predictor variable. In com-
paring fit of different spline models, we used 4 fit indices: the
generalized cross-validation criterion, the Akaike informa-
tion criterion, the Akaike information criterion corrected 1, and
the Bayesian information criterion.34-39 Analyses were per-
formed using commercial software (SAS, version 9.2, with
PROC LOESS and PROC NLIN; SAS Institute Inc).
Results
Descriptive Characteristics
The total duration of illness (psychotic or mood episodes) ranged
from 2 days to 4 years. On average, participants were in an epi-
sode for a mean (SD) of 48.4% (39.0%) of the follow-up period.
The distribution of psychosis duration was U-shaped (Supple-
ment [eFigure 2]); 28.7% of participants were psychotic briefly
(<5% of the follow-up period), 18.4% were psychotic con-
stantly (>95%), and 52.9% were between these subgroups. The
distribution of mania/hypomania was L-shaped: 58.6% had none
in the interval, and others were spread across the entire spec-
trum of duration. Depression had a similar distribution, with
31.4% of the participants not depressed and others spread across
the entire spectrum. The nonaffective psychosis ratio was U-
shaped: 51.3% of the patients were psychotic only while in mood
episodes, 20.7% had only nonaffective psychosis, and 28.0% had
psychosis both in and outside of mood episodes.
Ten-year outcomes ranged widely: GAF scores from 21 to
90, GAF-F from 30 to 90, and GAS from 25 to 90. Distributions
were positively skewed with modes in the low 40s. On SADS,
35.2% of participants were rated marked; 20.0%, moderate;
15.2%, mild; and 29.5%, remitted (returned to highest func-
tioning).
Linear and Nonlinear Associations With Outcome
First, we examined linear associations between the 4 symp-
tom course variables and the 4 outcomes by conducting mul-
tiple regression analyses, with the 4 predictors entering si-
multaneously and each outcome serving as the dependent
variable in turn. The strongest predictor was psychosis dura-
tion ( = 0.34 to 0.40), followed by nonaffective psychosis
(0.21 to 0.31) and finally depression (0.13 to 0.21); coef-
ficients for mania were not significant (Table 2). Zero-order cor-
relations are given in the Supplement (eMethods).
To test for nonlinearity of these associations, we esti-
mated LOESS models and compared them with linear mod-
els. The LOESS smoothed scatterplots for each predictor out-
come pair and took whatever shape summarized the data best.
For psychosis and depression, LOESS showed no improve-
ment over the linear model: change in fit was small and non-
significant (Supplement [eTable]). For mania and nonaffec-
tive psychosis, LOESS was significantly superior across all
outcomes, and the improvement in fit ranged from Akaike In-
formation Criterion Corrected 1 of 6.69 (substantial) to 51.57
(very substantial). Consistent with the fit indices, LOESS curves
for psychosis and depression were essentially linear (Figure 1).
Mania curves had an initial rise that plateaued and then gradu-
ally returned to the starting level. Nonaffective psychosis
curves showed an initial drop that soon leveled. An apparent
discontinuity in nonaffective psychosis contradicted the con-
tinuum model and was most consistent with the kraepelin-
ian model. However, more rigorous modeling was needed to
understand the exact form of the nonlinearity.
Spline Models
We used spline regression to more precisely evaluate nonlin-
earity detected by LOESS for nonaffective psychosis and ma-
nia. Psychosis and depression were not considered further be-
cause their associations with outcomes were purely linear.

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 Boundaries of Schizoaffective Disorder Original Investigation Research

Figure 1. Locally Weighted ScatterplotSmoothed Curves for Global Assessment of Functioning (GAF) and 4 Predictors

75 75

65 65
GAF Score

GAF Score
55 55

45 45

35 35
0 20 40 60 80 100 0 20 40 60 80 100
Psychosis, % Mania, %

75 75

65 65
GAF Score

GAF Score
55 55

45 45

35 35
0 20 40 60 80 100 0 20 40 60 80 100
Depression, % Nonaffective Psychosis Ratio, %

Dashed lines are 95% confidence band around the curve.

Spline regression allowed us to specify basic shapes of the Diagnostic Comparisons

curves to test target models and likely alternatives (Supple-
ment [eMethods]).
For nonaffective psychosis, the fit indices consistently sup-
ported the kraepelinian model across the outcomes (Table 3).
The only exception was GAS, for which 3 indices favored the
DSM-IV model, but the fit of the kraepelinian model was nearly
identical and superior on the Bayesian Information Criterion
the most parsimonious index. We named the identified groups
nonaffective psychosis absent and nonaffective psychosis pres-
ent. The boundary between them was at 1.5% of nonaffective
psychosis ratio, that is, 10 days of psychosis outside of mood
episodes (Figure 2).
For mania, the fit indices consistently supported the 3-group
model over all alternatives (Table 3). The only exception was
SADS, for which 3 indices favored the 4-group model, but fit of
the 3-group model was nearly identical and the Bayesian Infor-
mation Criterion favored 3 groups. We named the 3 groups ma-
nia absent, episodic mania, and chronic mania. The boundaries
between them were 0.8% (11 days) and 27.0% (394 days) manic
(Figure 2). In the episodic group, elevated mood consisted pri-
marily of mania (mean, 65.4% of time in episodes), with the rest
being mixed state (23.5%) or hypomania (11.1%). In the chronic
group, mania (35.0%), mixed state (37.3%), and hypomania
(27.7%) were evenly represented. The selected spline models fit
the data much better than LOESS, indicating further support for
these specific types of nonlinearity.
Next, we examined concordance between empirical groups
identified by spline regression and DSM-IV diagnoses. Be-
cause diagnoses were assigned at the 2-year point, we scored
empirical groups from the first 2 years of course data using the
aforementioned cutoffs (1.5% on nonaffective psychosis, and
0.8% and 27.0% on mania).
Overall, concordance between the empirical groups and
DSM-IV diagnoses was high. Nearly all (88.6) participants with
schizophrenia or schizoaffective disorder diagnosis were in the
nonaffective psychosis present group (Table 4); those who were
assigned to nonaffective psychosis absent either had nonaf-
fective psychosis before the first hospitalizationincluding the
5 schizoaffective casesor had prominent negative symp-
toms outside mood episodes. Almost all (97.3%) cases of psy-
chotic mood disorders were in the nonaffective psychosis ab-
sent group; the remaining 2.7% had only brief periods of
nonaffective psychosis and their mood symptoms were much
more severe than psychotic symptoms, resulting in psychotic
mood disorder diagnosis.
Of participants with bipolar disorder, 20.7% were in the
chronic mania group. Others were in the episodic mania group,
except for 4 patients who had mania only before the first hos-
pitalization and thus were classified in the absent group. Ap-
proximately half (53.8%) of participants with schizoaffective
disorder diagnosis were in the episodic or chronic group. Ma-
nia was rare in other disorders.

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 Research Original Investigation Boundaries of Schizoaffective Disorder

Table 3. Comparison of Spline Regression Modelsa

Global Assessment
Functioning (Overall) Functional Performance Symptoms Psychosocial Functioning
Predictor/Outcome GCV AICC1 AIC BIC GCV AICC1 AIC BIC GCV AICC1 AIC BIC GCV AICC1 AIC BIC
Nonaffective psychosis
LOESSb 0.588 2684 2268 2282 0.548 2624 2212 2226 0.601 2625 2218 2232 0.00325 553 130 143
2 Flat (kraepelinian)c 0.581 2678 2261 2265 0.539 2618 2205 2209 0.595 2621 2213 2217 0.00319 544 120 124
3 Flat (DSM-IV) 0.584 2680 2263 2271 0.541 2619 2206 2214 0.593 2619 2211 2219 0.00320 546 122 130
2 Linear 0.585 2681 2266 2278 0.542 2620 2209 2221 0.598 2623 2216 2229 0.00321 548 126 138
3 Linear 0.590 2685 2268 2284 0.544 2622 2213 2233 0.597 2622 2216 2228 0.00328 557 128 140
1 Quadratic + 1 linear 0.588 2684 2266 2278 0.541 2620 2211 2227 0.601 2625 2217 2229 0.00323 550 127 144
2 Quadratic + 1 linear 0.593 2687 2270 2290 0.549 2625 2212 2232 0.606 2628 2220 2240 0.00326 555 131 151
1 Cubic + 1 linear 0.585 2681 2270 2290 0.544 2622 2211 2227 0.604 2627 2219 2235 0.00323 550 129 150
Mania
LOESS 0.577 2676 2258 2282 0.548 2625 2212 2237 0.615 2635 2227 2254 0.00342 575 151 178
2 Flat 0.596 2689 2272 2276 0.560 2634 2221 2225 0.628 2642 2234 2238 0.00345 578 154 158
3 Flat 0.561 2664 2247 2255 0.538 2617 2204 2212 0.603 2626 2218 2226 0.00336 567 143 151
4 Flat 0.566 2668 2251 2263 0.539 2618 2205 2217 0.608 2630 2221 2233 0.00335 566 142 154
2 Linear 0.576 2675 2262 2270 0.546 2623 2214 2222 0.613 2633 2229 2237 0.00343 576 152 160
3 Linear 0.569 2670 2259 2279 0.541 2619 2206 2218 0.607 2629 2223 2239 0.00336 567 143 155
4 Linear 0.580 2678 2261 2277 0.539 2618 2211 2231 0.614 2634 2226 2242 0.00338 569 145 161
1 Quadratic + 1 linear 0.589 2684 2269 2285 0.566 2638 2227 2243 0.625 2641 2235 2251 0.00340 572 150 166
2 Quadratic + 1 linear 0.570 2671 2260 2288 0.539 2618 2211 2235 0.611 2632 2224 2244 0.00341 573 151 167
1 Cubic + 1 linear 0.591 2686 2271 2287 0.576 2645 2234 2250 0.635 2647 2241 2257 0.00353 587 163 179
39
Abbreviations: AIC, Akaike information criterion; AICC1, Akaike information substantial, and greater than 10 is very substantial.
criterion corrected 1; BIC, Bayesian information criterion; GCV, generalized cross b
LOESS uses weighted least squares to fit linear functions within a fixed
validation criterion; LOESS, locally weighted scatterplot smoothing. neighborhood of each data point, as determined by the smoothing parameter
a
Bold indicates best fit of the series. These indices are derived from different (percentage of the sample included). We examined a range of smoothing
statistical theories and are scaled differently.34,36,38,39 However, all 4 can be parameters and selected 60%, as greater inclusion did not increase fit of the
decomposed into 2 components: a measure of fit between the model and data curve.
and a penalty for model complexity. Based on the latter, the indices can be c
Polynomials of degree 0, 1, 2, or 3 (flat, linear, quadratic, or cubic function)
ordered from least to most parsimonious: AIC, GCV, AICC1, and BIC. There are were fit onto each segment. Other than the flat function regressions, all
no absolute cutoffs on these indices, but they can be used to compare models, regressions were restricted to be continuous. The locations of break points
with lower values representing better fit.38,39 Conventional guidelines suggest and the slope of each segment were freely estimated.
that on AIC, AICC1, and BIC, a difference less than 6 is small, 6 to 10 is

With regard to outcomes, nonaffective psychosis present
had notably worse scores than nonaffective psychosis absent
(Table 4). The differences were more than 10 points on GAF,
GAF-F, and GAS, and one level on SADS (ie, between moder-
ate and mild condition). Similar differences were observed be-
tween mania absent and episodic mania. In contrast, the
chronic mania group was similar to mania absent on all out-
comes. Outcomes for DSM-IV schizoaffective disorder were
similar to those of nonaffective psychosis present, whereas out-
comes for schizophrenia were slightly worse (4-5 points on GAF
metric). Participants with bipolar disorder did about as well
as the episodic mania group.
Discussion
Using modern statistical techniquesLOESS and spline regres-
sionwe detected strong nonlinearity in the relationship be-
tween ratio of nonaffective psychosis to mood disturbance and
later outcome in our first-admission cohort with psychotic dis-
orders. Specifically, we observed a qualitative difference in out-
come between cases in which psychosis is limited to mood epi-
sodes and c ases in which at least some psychosis is
nonaffective. No other discontinuities emerged in analyses of
nonaffective psychosis. These findings clearly support the krae-
pelinian dichotomy over the DSM-IV and continuum ac-
counts. We found no evidence of a distinct schizoaffective dis-
order. Judged by outcome, this diagnosis appears to be a part
of the schizophrenia spectrum. Other definitions of schizoaf-
fective disorder that do not rely on nonaffective psychosis are
possible and were not evaluated here. The analyses also re-
vealed 2 distinct types of mania: episodic and chronic. In con-
trast, duration of psychosis and depression both had linear as-
sociations with outcomes and did not demarcate natural
boundaries within psychotic disorders.
If replicated in other samples and with other validators, our
results would have several implications for future editions of
the DSM. Given the lack of validity of schizoaffective disorder
diagnosis observed in this study and questionable support in
the literature,7,40,41 continued use of this category is difficult to
justify. Indeed, prior research7-20 considered various valida-
tors: phenotypic, outcome, cognitive, neural, and genetic, and

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 Boundaries of Schizoaffective Disorder Original Investigation Research

Figure 2. Curves for the Best-Fitting Spline Models for Each Outcome

75 75

65 65
GAF Score

GAF Score
55 55

45 45

35 35
0 20 40 60 80 100 0 20 40 60 80 100
Nonaffective Psychosis Ratio, % Mania, %

75 75

65 65
GAF-F Score

GAF-F Score
55 55

45 45

35 35
0 20 40 60 80 100 0 20 40 60 80 100
Nonaffective Psychosis Ratio, % Mania, %

75 75

65 65
GAS Score

GAS Score

55 55

45 45

35 35
0 20 40 60 80 100 0 20 40 60 80 100
Nonaffective Psychosis Ratio, % Mania, %

4 4

3 3
SADS Score

SADS Score

2 2

1 1
0 20 40 60 80 100 0 20 40 60 80 100
Nonaffective Psychosis Ratio, % Mania, %

Outcome expected at each level of symptom is shown. GAF indicates Global Assessment of Functioning; GAF-F, Global Assessment of Functional Performance; GAS,
Global Assessment of Symptoms; and SADS, Schedule for Affective Disorders and Schizophrenia.

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 Research Original Investigation Boundaries of Schizoaffective Disorder

Table 4. DSM-IV Diagnoses, Empirical Groups, and Outcomesa

No. (%) Outcomes, Mean (SD)

Nonaffective Psychosis
Groups Mania Groups Global Assessment
Functional Psycho-
Functioning Perfor- social
Group Absent Present Absent Episodic Chronic (Overall) mance Symptoms Functioning
Primary DSM-IV diagnosis
Schizophrenia 19 (10.3) 165 (89.7) 159 (86.4) 21 (11.4) 4 (2.2) 44.7 (11.0) 46.8 (11.2) 45.9 (12.4) 1.6 (0.9)
Schizoaffective 5 (19.2) 21 (80.8) 12 (46.2) 10 (38.5) 4 (15.4) 49.4 (14.8) 52.6 (12.9) 51.4 (15.0) 2.0 (1.2)
Bipolar with psychosis 131 (97.0) 4 (3.0) 4 (3.0) 103 (76.3) 28 (20.7) 65.2 (15.2) 67.8 (13.7) 68.7 (13.6) 3.1 (1.1)
MDD with psychosis 89 (97.8) 2 (2.2) 91 (100) 0 0 58.0 (14.8) 61.9 (14.5) 62.4 (13.8) 2.7 (1.2)
Other psychoses 36 (40.9) 52 (59.1) 68 (77.3) 11 (12.5) 9 (10.2) 57.8 (16.1) 60.3 (15.6) 59.9 (15.6) 2.7 (1.2)
Nonaffective psychosis group
Absent NA NA 134 (47.9) 111 (39.6) 35 (12.5) 59.6 (15.8) 62.8 (15.0) 62.9 (15.1) 2.9 (1.2)
Present NA NA 201 (81.7) 35 (14.2) 10 (4.1) 49.1 (14.8) 50.9 (14.4) 50.5 (15.5) 1.9 (1.1)
Mania group
Absent NA NA NA NA NA 51.3 (15.1) 53.6 (15.4) 53.6 (16.0) 2.2 (1.2)
Episodic NA NA NA NA NA 62.8 (15.9) 65.8 (14.4) 65.6 (15.2) 2.9 (1.2)
Chronic NA NA NA NA NA 54.1 (15.5) 57.5 (13.4) 57.7 (14.6) 2.5 (1.1)

Abbreviations: MDD, major depressive disorder; NA, not applicable. mania); dichotomous outcomes are presented as row percentages; diagnosis
a
Number of patients: 280 (nonaffective psychosis absent), 246 (nonaffective was made at 2-year point; nonaffective psychosis and mania groups were
psychosis present), 335 (mania absent), 146 (episodic mania), and 45 (chronic scored based on illness course between baseline and 2-year point.

only 9 of 256 studies of this question concluded that schizoaf-
fective disorder is a distinct condition.40 Our findings suggest
that patients who currently are assigned a diagnosis of schi-
zoaffective disorder would be better described as having schizo-
phrenia (or schizophreniform disorder) with comorbid mood dis-
order. This nosologic change would reflect a growing recognition
of the important role that mood comorbidities play in
schizophrenia42-44 and permit a flexible classification of psy-
chotic illnesses without invoking an apparently arbitrary diag-
nostic category. Continuous ratings of severity for mood disor-
ders and schizophrenia could further increase informational
value of such a classification. Indeed, such ratings have been
proposed for the DSM-5. With regard to schizoaffective diag-
nosis, the only significant revision considered for the DSM-5 is
to make it explicitly a lifetime diagnosis,45 and this is how the
disorder was approached in the present study. Our findings ar-
gue for reconsideration of schizoaffective disorder, but more re-
search is needed.
In contrast, we found a clear discontinuity between schizo-
phrenia spectrum disorders and psychotic mood disorder. In
our data, even 10 days of nonaffective psychosis resulted in a
qualitatively worse outcome. This is consistent with DSM-IV
criteria for demarcating schizoaffective disorder and psy-
chotic mood disorder (ie, 2 weeks of nonaffective psychosis).
Bipolar disorder with psychosis also was clearly distin-
guished from other psychotic disorders, even with several days
of manic symptoms forecasting qualitatively better out-
comes. This finding is consistent with research10,16,17 indicat-
ing favorable outcomes for this disorder relative to other psy-
choses. In addition, we observed a discontinuity within the
bipolar spectrum, suggesting existence of a chronic mania sub-
type defined by being manic for at least a year. This subtype
has prognostic significance because it was associated with a
distinctly worse outcome. Of note, all of these findings were
consistent across several outcome measures, strengthening
conclusions of the study. These measures reflect a single vali-
datorglobal outcomeand are not independent replica-
tions, but they helped to ensure that the present results are
not due to characteristics of a particular rating scale.
We did not hypothesize the chronic mania group a priori,
and it requires confirmation, but this finding aligns well with
the extant literature. Chronic mania was recognized as a dis-
tinct category in the 19th century.46 More recently, it has been
operationalized as a manic episode lasting at least 2 years, and
6% to 13% of patients with bipolar I disorder fit this subtype.46
Of note, the 2-year definition of chronic mania was proposed
based on a zone of rarity in distribution of episode length, but
the zone ranged from 1 to 2 years.47 By the 1-year definition,
prevalence of chronic mania is approximately 15%,48 which is
comparable to the estimate in our cohort (20.7% of bipolar I
disorder).
The observed empirical groups were defined by symp-
toms only. Nevertheless, both nonaffective psychosis and ma-
nia categories showed the anticipated convergence with
DSM-IV diagnoses. There was only a handful of inconsisten-
cies resulting from symptoms present before the first hospi-
talization or to highly prominent symptoms that received spe-
cial weight in diagnostic decision making. In addition, mania
groups included some patients with schizophrenia and other
psychoses, which reflects the presence of comorbid mood dis-
orders in these cases.
These empirical groupings had substantial predictive va-
lidity, forecasting more than 10-point differences in GAF among
both nonaffective psychosis and mania groups years later. The
DSM-IV diagnosis was somewhat more predictive, with schizo-
phrenia outcome being 5 GAF points lower than the nonaffec-

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 Boundaries of Schizoaffective Disorder Original Investigation Research

tive psychosis present group. Schizophrenia diagnosis explic-
itly requires marked deterioration of functioning (criterion B),
which likely explains why this group fared worse than the non-
affective psychosis present group. Altogether, it is remark-
able that simple classification rules based solely on symptom-
atology were almost as predictive as full DSM-IV diagnosis.
The observed sharp distinction between no nonaffective
psychosis and any nonaffective psychosis and the large effect
it had on outcome suggests differences in etiologies of these
groups. For instance, psychotic symptoms in schizophrenia
spectrum disorders may result from neurodevelopmental
pathologic factors, whereas psychosis in psychotic mood dis-
order may be induced by stress.49,50 These findings contra-
dict the continuum view of psychotic disorders, but psy-
chotic mood disorder and nonaffective psychosis may share
some risk factors and pathophysiologic processes. Many such
commonalities have been documented51,52 and may explain
their substantial comorbidity.42-44 In our sample, 57% of the
nonaffective psychosis group experienced at least one mood
episode. The degree of overlap versus distinction among these
conditions can be further explicated by applying nonlinear
modeling to other validators.
Our rejection of the 3-disorder model in favor of the krae-
pelinian dichotomy seems to be at odds with studies15,16 re-
porting better outcomes in schizoaffective disorder compared
with schizophrenia. Importantly, schizoaffective disorder is
defined only by symptom pattern and, unlike schizophrenia,
does not require marked functional impairment or 6-month
duration, which likely explains differences in outcome. In-
deed, in our cohort, outcome of schizoaffective disorder was
no different from the outcome of the rest of the nonaffective
psychosis group. Quantitative distinctions among patients
with psychotic disorders also must be recognized. We found
that of all variables considered, duration of psychosis was the
most important predictor of outcome. Clinicians need to re-
main vigilant to long-term disability associated with chronic
psychosis.
Strengths of this investigation include a first-admission epi-
demiologic cohort that was followed long-term and a pains-
taking tracking of symptoms and functioning using inter-
views, informant reports, and medical records. Nevertheless,
the present findings need to be considered against the studys
limitations. First, detailed documentation of symptoms was
limited to 4 years and sometimes did not include illness on-
set. This investigation targeted a crucially important period of
illness course, but close tracking of symptoms over a long term
would provide a more definitive test of diagnostic boundar-
ies. Second, validation of diagnostic distinctions was limited
to long-term outcome. Kraepelin1,2 considered illness course
the key consideration for diagnostic validity, but a compre-
hensive evaluation has to include other characteristics, such
as genetic risk factors, neural substrates, and treatment
response.53 This effort requires integration of findings from dif-
ferent research paradigms, and the present study is a step to-
ward this goal. Third, the present report focused on global out-
comes, as these have been the primary benchmarks for other
longitudinal studies of schizoaffective disorder.15,17,18 We also
collected fine-grained information and will investigate spe-
cific outcomes in subsequent studies. Fourth, each outcome
was a single rating, and such variables tend to have low reli-
ability. To ensure strong psychometric properties, the pres-
ent ratings were made by consensus of research psychiatrists
based on all available information. Fifth, consensus diagno-
sis was available at the 2-year rather than 4-year point, so we
had to limit analyses comparing diagnoses and empirical
groups to 2 years of symptom course. Sixth, we could not in-
vestigate treatment effects in this naturalistic study, and it is
important to confirm present findings in randomized trials,
controlling for treatment experiences. Finally, generalizabil-
ity of the present results was limited by attrition. Fortunately,
attrition during the 10-year study was modest and had little
effect on study variables.
In conclusion, if replicated, our findings would provide
clear support for the kraepelinian dichotomy, and this sharp
boundary presents a significant challenge for the continuum
view of psychotic disorders. Also, absence of the boundary be-
tween schizophrenia and schizoaffective disorder calls valid-
ity of the latter into question. Schizoaffective disorder was an
early advance that recognized the co-occurrence of schizo-
phrenia and mood disorders. It was an imperfect solution, how-
ever, and the present findings suggest that coding of comor-
bid schizophrenia (or schizophreniform disorder) and mood
disorder as 2 separate diagnoses may serve the field better than
the schizoaffective category. In fact, the DSM-IV already per-
mits such coding, and this proposal would extend it to cases
currently diagnosed as schizoaffective disorder. This change
also would streamline differential diagnosis for psychotic dis-
orders. Indeed, the reliability of schizoaffective disorder di-
agnosis is remarkably poor.26,54 Much of this difficulty stems
from criterion C,54 which separates schizoaffective disorder
from schizophrenia with comorbid mood disorder. Our re-
sults suggest that this distinction is superfluous, which may
explain the associated unreliability. Thus, by abolishing the
schizoaffective disorder category while maintaining the quali-
tative distinction between psychotic mood disorder and schizo-
phrenia spectrum disorders, it may be possible to align the no-
sology with the natural taxonomy of psychoses, simplify
diagnosis, and improve its reliability. This contention re-
quires verification in other samples and with a variety of vali-
dators.

ARTICLE INFORMATION
Submitted for Publication: November 15, 2012;
final revision received February 6, 2103; accepted
April 2, 2013.
Published Online: October 2, 2013.
doi:10.1001/jamapsychiatry.2013.2350.
Author Contributions: Dr Kotov takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Kotov, Mojtabai, Carlson.
Acquisition of data: Kotov, Fochtmann,
Constantino, Bromet.
Analysis and interpretation of data: Kotov, Leong,
Mojtabai, Erlanger.
Drafting of the manuscript: Kotov, Leong, Erlanger,
Bromet.
Critical revision of the manuscript for important
intellectual content: Leong. Mojtabai, Erlanger,
Fochtmann, Constantino, Carlson, Bromet.
Statistical analysis: Kotov, Leong.
Obtained funding: Kotov, Bromet.

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 Research Original Investigation
Administrative, technical, and material support:
Kotov, Erlanger.
Study supervision: Kotov, Erlanger, Bromet.
Conflict of Interest Disclosures: None reported.
Funding/Support: National Institutes of Health
grant MH094398 to Dr Kotov and MH44801 to Dr
Bromet.
Role of the Sponsor: The National Institutes of
Health had no role in the design and conduct of the
study; collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Additional Contributions: Greg Perlman, PhD,
Adam Gonzalez, PhD, and Camilo Ruggero, PhD,
provided feedback on the manuscript. We thank
the mental health professionals in Suffolk County,
the project psychiatrists and staff, and most of all,
the study participants and their families and
friends. The project psychiatrists and staff received
their usual salary support; no others were paid for
their services.
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