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Articles   |    
Clinical Phenotypes of Psychosis in the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP)
Carol A. Tamminga, M.D.; Elena I. Ivleva, M.D., Ph.D.; Matcheri S. Keshavan, M.D.; Godfrey D. Pearlson, M.D.; Brett A. Clementz, Ph.D.; Bradley Witte, B.S.; David W. Morris, Ph.D.; Jeffrey Bishop, Ph.D.; Gunvant K. Thaker, M.D.; John A. Sweeney, Ph.D.
Am J Psychiatry 2013;170:1263-1274. doi:10.1176/appi.ajp.2013.12101339
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Dr. Pearlson reports serving as a consultant for Bristol-Myers Squibb in 2012. Dr. Bishop reports receiving research support from Ortho-McNeil Janssen. Dr. Sweeney reports serving on advisory boards to Bristol-Myers Squibb, Eli Lilly, Pfizer, Roche, and Takeda and receiving a research grant from Janssen. Disclosures for Dr. Tamminga, as a Deputy Editor of the American Journal of Psychiatry, were published in the January issue. Drs. Ivleva, Keshavan, Clementz, Morris, and Thaker and Mr. Witte report no financial relationships with commercial interests.

Supported by NIMH grants MH-077851 (Dr. Tamminga), MH-078113 (Dr. Keshavan), MH-077945 (Dr. Pearlson), MH-077852 (Dr. Thaker), and MH-077862 (Dr. Sweeney).

From the Department of Psychiatry, University of Texas Southwestern Medical School, Dallas; the Department of Psychiatry, Beth Israel Deaconess Hospital, Harvard Medical School, Boston; the Institute of Living, Hartford, Conn.; the Department of Psychiatry, Yale School of Medicine, New Haven, Conn.; the Department of Psychology, University of Georgia, Athens; the Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore; and the University of Illinois School of Pharmacy, Chicago.

Address correspondence to Dr. Tamminga (carol.tamminga@utsouthwestern.edu).

Copyright © 2013 by the American Psychiatric Association

Received October 21, 2012; Revised February 13, 2013; Accepted March 18, 2013.

Abstract

Objective  Developing categorical diagnoses that have biological meaning within the clinical phenotype of psychosis (schizophrenia, schizoaffective disorder, and bipolar I disorder with psychosis) is as important for developing targeted treatments as for nosological goals. The Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) was formed to examine a broad array of intermediate phenotypes across psychotic disorders and to test the hypothesis that intermediate phenotype characteristics are homogeneous within phenomenologically derived DSM-IV diagnoses.

Method  The consortium recruited 933 stable probands with schizophrenia, schizoaffective disorder, or psychotic bipolar I disorder, 1,055 of their first-degree relatives, and 459 healthy comparison subjects for clinical characterization and dense phenotyping. Clinical, psychosocial, and family characteristics were contrasted.

Results  All proband groups showed lower psychosocial functioning than the relatives or comparison group. On average, schizophrenia probands showed more symptoms and lower psychosocial functioning than probands with psychotic bipolar disorder, but there was considerable overlap in clinical manifestations. The characteristics of schizoaffective disorder were more often similar to schizophrenia than to psychotic bipolar disorder. The rates of lifetime suicide attempts were high across all proband groups, with the highest reported frequencies in the schizoaffective and bipolar groups. Proband family lineages included both families with “pure” psychosis diagnoses and families with mixed schizophrenia-bipolar diagnoses.

Conclusions  Symptoms, psychosocial functioning, and familial lineage overlap across the three DSM-IV psychosis diagnoses used in B-SNIP. The comingling of psychosis diagnoses within families suggests overlapping genetic determinants across psychoses. These data provide scant evidence for distinct phenotypic clustering around traditional phenomenological diagnoses.

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FIGURE 1. Scores for Symptoms of Schizophrenia, Mania, and Depression in Probands With Schizophrenia, Schizoaffective Disorder, or Psychotic Bipolar I Disorder

a Significant difference across groups (F=68.22, df=2, 835, p<0.001). Tukey-Kramer post hoc test results (p<0.01): schizophrenia and schizoaffective disorder probands different from bipolar probands.

b Significant difference across groups (F=67.88, df=2, 836, p<0.001). Tukey-Kramer post hoc test results (p<0.01): schizophrenia and schizoaffective disorder probands different from bipolar probands.

c Significant difference across groups (F=76.57, df=2, 836, p<0.001). Tukey-Kramer post hoc test results (p<0.01): schizophrenia and schizoaffective disorder probands different from bipolar probands.

d Significant difference across groups (F=32.07, df=2, 837, p<0.001). Tukey-Kramer post hoc test results (p<0.01): schizophrenia and schizoaffective disorder probands different from bipolar probands.

e Significant difference across groups (F=6.69, df=2, 828, p=0.001). Tukey-Kramer post hoc test results (p<0.01): schizoaffective disorder probands different from schizophrenia probands.

f Significant difference across groups (F=31.00, df=2, 834, p<0.001). Tukey-Kramer post hoc test results (p<0.01): schizoaffective disorder probands different from schizophrenia and bipolar disorder probands.

FIGURE 2. Distribution of Scores for Schizophrenia Symptoms and Social Functioning in Probands With Schizophrenia, Schizoaffective Disorder, or Psychotic Bipolar I Disordera

a The whisker plots show the group median within the box, with the limits of the box demonstrating the 25th and 75th percentiles of values and the vertical bars indicating the 5th and 95th percentiles, thus demonstrating the overlap of the distributions.

b On the PANSS total rating, 98.9% of the schizoaffective disorder probands and 100.0% of the bipolar probands had scores within 2 standard deviations of the scores for the probands with schizophrenia.

c On the Birchwood Social Functioning Scale, 90.1% of the schizoaffective disorder probands and 94.6% of the bipolar probands had scores within 2 standard deviations of the scores for the schizophrenia probands.

FIGURE 3. Scores on the Birchwood Social Functioning Scale for Probands With Schizophrenia, Schizoaffective Disorder, or Psychotic Bipolar I Disorder, Their Relatives, and Healthy Comparison Subjects

a Significant difference among groups (one-way ANOVA) for social engagement/withdrawal (F=67.44, df=6, 2172, p<0.001), interpersonal communication (F=77.80, df=6, 2166, p<0.001), independence/competence (F=35.84, df=6, 1921, p<0.001), independence/performance (F=74.39, df=6, 2103, p<0.001), recreational activities (F=37.37, df=6, 2118, p<0.001), prosocial performance (F=55.66, df=6, 2093, p<0.001), and employment/occupation (F=103.38, df=6, 2097, p<0.001).

b Significant difference (one-way ANOVA) among groups (F=99.97, df=6, 1755, p<0.001).

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TABLE 1.Sociodemographic Characteristics of Probands With Schizophrenia, Schizoaffective Disorder, or Psychotic Bipolar I Disorder, Their Relatives, and Healthy Comparison Subjectsa
Table Footer Note

a The largest numbers of subjects available for each study group are presented. Percentages for dichotomous variables were based on the number of subjects available for each group excluding missing data. Proportions of missing data ranged from 0.8% to 11.0% for various sociodemographic characteristics.

Table Footer Note

b Significant overall difference (F=15.28, df=6, 2427, p<0.001). The relatives were older than the probands and comparison subjects. Tukey-Kramer post hoc test results (p<0.01): schizophrenia probands different from all three relative groups; probands with schizoaffective disorder different from schizophrenia relatives; bipolar probands different from schizophrenia relatives; schizophrenia relatives different from all three proband groups and comparison group; schizoaffective disorder relatives different from schizophrenia probands; bipolar disorder relatives different from schizophrenia probands and comparison group; comparison group different from schizophrenia and schizoaffective disorder relatives.

Table Footer Note

c Significant overall difference (F=31.69, df=6, 2336, p<0.001). The comparison group had the highest education level, the bipolar probands had more education than the other proband groups, and relatives had more education than probands. Tukey-Kramer post hoc test results (p<0.01): schizophrenia probands different from bipolar probands, all three relative groups, and comparison group; schizoaffective disorder probands different from bipolar probands, schizoaffective and bipolar disorder relatives, and comparison group; bipolar probands different from other two proband groups and comparison group; schizophrenia relatives different from schizophrenia and schizoaffective disorder probands and comparison group; schizoaffective disorder relatives different from schizophrenia probands, bipolar disorder relatives, and comparison group; bipolar disorder relatives different from schizophrenia and schizoaffective disorder probands and from schizoaffective disorder relatives; comparison group different from schizophrenia, schizoaffective disorder, and bipolar disorder probands and from schizophrenia and schizoaffective disorder relatives.

Table Footer Note

d Significant overall difference (χ2=151.01, df=6, p<0.001).

Table Footer Note

e Significant overall difference (χ2=129.89, df=12, p<0.001).

Table Footer Note

f Significant overall difference (χ2=253.79, df=18, p<0.001).

Table Footer Note

g Significant overall difference (χ2=278.74, df=24, p<0.001).

Table Footer Note

h Nonsignificant overall difference (χ2=39.09, df=24, p=0.03).

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TABLE 2.Clinical Characteristics of Probands With Schizophrenia, Schizoaffective Disorder, or Psychotic Bipolar I Disorder, Their Relatives, and Healthy Comparison Subjectsa
Table Footer Note

a The largest numbers of subjects available for each study group are presented. Percentages for the dichotomous variable were based on the number of subjects available for each group excluding missing data. Proportions of missing data ranged from 0.3% to 19.9% for various clinical characteristics.

Table Footer Note

b Significant overall difference (F=9.65, df=6, 2186, p<0.001). Tukey-Kramer post hoc test results (p<0.01): schizophrenia probands different from bipolar probands and relatives and from comparison group; schizoaffective disorder probands different from bipolar disorder relatives and comparison group; bipolar probands different from schizophrenia probands; schizophrenia relatives different from bipolar relatives and comparison group; bipolar relatives different from schizophrenia and schizoaffective disorder probands and from schizophrenia relatives; comparison group different from schizophrenia and schizoaffective disorder probands and from schizophrenia relatives.

Table Footer Note

c Significant overall difference (F=441.02, df=6, 2269, p<0.001). Tukey-Kramer post hoc test results (p<0.01): schizophrenia probands different from bipolar probands, all three relative groups, and comparison group; schizoaffective disorder probands different from bipolar probands, all three relative groups, and comparison group; bipolar disorder probands different from all other groups; schizophrenia relatives different from all proband groups and from comparison group; schizoaffective disorder relatives different from all proband groups and from comparison group; bipolar disorder relatives different from all proband groups; comparison group different from all other groups.

Table Footer Note

d Nonsignificant difference among groups (F=2.23, df=2, 842, p=0.11).

Table Footer Note

e Nonsignificant difference among groups (F=2.06, df=2, 762, p=0.13).

Table Footer Note

f Nonsignificant difference among groups (F=0.87, df=2, 695, p=0.42).

Table Footer Note

g Significant overall difference (χ2=21.56, df=2, p<0.001).

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TABLE 3.Frequencies of Lifetime DSM-IV Psychiatric Disorders in Relatives of Probands With Schizophrenia, Schizoaffective Disorder, or Psychotic Bipolar I Disorder
Table Footer Note

a Assessed with Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition (30).

Table Footer Note

b Assessed with Structured Interview for DSM-IV Personality Disorders (35).

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TABLE 4.Family History of Psychiatric Disorders in Probands With Schizophrenia, Schizoaffective Disorder, or Psychotic Bipolar I Disorder
+

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