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 page 1263 IMPORTANCE Established nosology identifies schizoaffective disorder as a distinct category with boundaries separating it from mood disorders with psychosis and from schizophrenia. 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. Author Audio Interview at jamapsychiatry.com Supplemental content at jamapsychiatry.com 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 discontinuity—10 days or more of psychosis outside mood episodes predicted an 11-point decrement in GAF—consistent 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 that could simplify diagnosis, improve its reliability, and align it with the natural taxonomy. JAMA Psychiatry. 2013;70(12):1276-1286. doi:10.1001/jamapsychiatry.2013.2350 Published online October 2, 2013. 1276 Author Affiliations: Department of 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 Brook University, Stony Brook, NY 11794 (roman.kotov@stonybrook.edu). jamapsychiatry.com Copyright 2013 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Montclair State Univ Lib User on 09/21/2020 Boundaries of Schizoaffective Disorder T Original Investigation Research he delineation of schizophrenia (dementia praecox) and psychotic mood disorders (manic-depressive insanity) as 2 distinct entities was one of Emil Kraepelin’s seminal contributions to nosology.1 More than 100 years later, this kraepelinian dichotomy remains highly influential.2 However, 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 subtype 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 absence of mood symptoms, and (C) mood episodes present for a substantial portion of illness duration. Thus, DSM-IV elaborates on the kraepelinian dichotomy by adding an intermediate condition, with criterion B defining its boundary with psychotic 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 prominent; and in schizophrenia, nonaffective psychosis predominates. 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 disorder using several basic approaches. Investigations of phenomenology found support for the continuum model,7 the kraepelinian 2-disorders model,8,9 and the DSM-IV 3-disorders model.10 Studies of neurobiological and cognitive functioning, as well as family and genetic research, reported evidence favoring the continuum7,11 and 3-disorders12-14 models. Longitudinal 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 recommendations for nosology. Some of these inconsistencies likely result from changes in schizoaffective diagnosis, which was defined more broadly by earlier diagnostic manuals. Among diagnostic validators, illness course is of particular interest. Indeed, it was most central to Kraepelin’s work because he sought to develop diagnoses that would be prognostic of future symptoms and functioning (ie, global outcome).2 Unfortunately, existing longitudinal studies were not designed 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 distinguish gradual differences (ie, a continuum) from qualitative changes (ie, natural boundaries). Indeed, in many studies15,16 outcome of schizoaffective disorder fell between that of schizophrenia and psychotic mood disorder, which is consistent with both the continuum and 3-disorders models. Kendell and Brockington21 proposed a solution to this problem. They examined associations between the spectrum ranging from typical psychotic mood disorder to typical schizophrenia and continuous outcome measures. Their hypothesis 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 inspection of graphs.22 The latter shortcoming might explain why this technique has not been widely adopted. More recent developments 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 statistical methods. We analyzed detailed symptom course data from an epidemiologic cohort of inpatients with psychosis monitored prospectively for 10 years after their first hospitalization. In particular, we examined links between nonaffective 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 boundary between psychotic mood disorder and the schizophrenia spectrum, and the DSM-IV model predicts 2 boundaries, one between psychotic mood disorder and schizoaffective disorder and another between schizoaffective disorder and schizophrenia (Supplement [eFigure 1]). In the latter 2 models, differences are expected between groups (eg, low nonaffective psychosis and high nonaffective psychosis), but no association is predicted between nonaffective psychosis and outcome within groups. We constructed statistical models to test these hypotheses. We also used this method to explore natural boundaries within depression and mania. Methods Participants Data for this study came from the Suffolk County Mental Health Project, an epidemiologic study of first-admission psychosis.24-26 Patients were recruited from the 12 psychiatric inpatient units of Suffolk County, New York, between October 1989 and December 1995. Inclusion criteria were first admission, either current or within 6 months; clinical evidence of psychosis; age 15 to 60 years; IQ higher than 70; proficiency with English; and no apparent general medical etiology. The study was approved annually by the institutional review boards of Stony Brook University and the participating hospitals. Treating physicians determined participants’ capacity 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 referrals); 628 of them met the eligibility criteria. By the 4-year point, 10 participants had died, 29 were untraceable, 41 refused further 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 assessment, 27 had died, 28 were untraceable, 41 refused further participation, and 17 provided insufficient outcome information; 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 jamapsychiatry.com JAMA Psychiatry December 2013 Volume 70, Number 12 Copyright 2013 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Montclair State Univ Lib User on 09/21/2020 1277 Research Original Investigation Boundaries of Schizoaffective Disorder Table 1. Demographic and Clinical Characteristics of the Sample No. (%)a Characteristic Total Cohort (N = 628) Course Sample (n = 526) Outcomes Sample (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) Schizophrenia/schizophreniform 199 (33.8) 184 (35.1) 145 (35.1) Schizoaffective 30 (5.1) 26 (5.0) 21 (5.1) Bipolar with psychosis 148 (25.1) 135 (25.8) 112 (27.1) DSM-IV diagnosis at year 2 Abbreviations: GAF, Global Assessment of Functioning; GAF-F, Global Assessment of Functional Performance; GAS, Global Assessment of Symptoms; MDD, major depressive disorder; NA, not applicable; SADS, Schedule for Affective Disorders and Schizophrenia; SES, socioeconomic status. MDD with psychosis 104 (17.7) 91 (17.4) 68 (16.5) Other psychoses 108 (18.3) 88 (16.8) 67 (16.2) % Psychosisb NA 36.4 (38.4) 37.4 (38.7) % Maniab NA 7.5 (18.6) 8.3 (19.9) % Depressionb NA 24.0 (32.6) 24.5 (32.8) % Nonaffective psychosis ratioc NA 35.7 (43.4) 34.9 (43.0) a Percentages may vary because of missing data. NA NA 54.8 (16.2) b NA NA 57.5 (15.9) Percentage of observed interval from baseline to 4-year point. c GAS NA NA 57.4 (16.5) Percentage of illness during interval from baseline to 4-year point. Psychosocial functioning (SADS) NA NA 2.4 (1.2) d Outcome at 10-year point. Symptom course, mean (SD) Outcome, mean (SD)d GAF GAF-F 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 overrepresentation of patients with low parental socioeconomic status in the former (P = 008). Measures Face-to-face assessments were conducted by master’s level mental health professionals at baseline, 6-month, 2-year, 4-year, and 10-year follow-up; telephone interviews were performed 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 significant others were also obtained at each major assessment. These detailed data allowed raters to chart symptom course between baseline and year 4. At least half of the interval was documented 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 separately and defined according to DSM-IV criteria except for duration, which we did not require. Episodes were scored as (1) percentage of the observed interval psychotic, (2) percentage of patients depressed, and (3) percentage of patients manic (including hypomania). Of particular interest was the nonaffective psychosis ratio, scored as percentage of illness psychotic and not in mood episode (illness was defined as mood or psy1278 chotic episode), because this ratio defines the diagnostic boundaries of schizoaffective disorder in DSM-IV (especially criterion C). Overall outcome is particularly relevant to validation of psychotic disorders.1,15,17,18 We examined 3 measures targeting its different aspects: Global Assessment of Symptoms (GAS) indicated overall symptom severity in the best month between 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 10year interview considering both symptoms and functioning. Each measure was rated on a 0 to 90 scale (with 10 anchors specific 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 reliability of consensus scores could not be assessed, but reliability of the individual raters was excellent, ranging intraclass 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- JAMA Psychiatry December 2013 Volume 70, Number 12 Copyright 2013 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Montclair State Univ Lib User on 09/21/2020 jamapsychiatry.com Boundaries of Schizoaffective Disorder Original Investigation Research Table 2. Multiple Linear Regression Analyses of 4-Year Course Predicting 10-Year Outcomes Global Assessment Functioning (Overall) Predictor/Outcome Intercept % Psychosis B β P Value 65.54 −16.20 Functional Performance B 69.05 −0.39
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