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Diffusion Tensor Imaging White Matter Endophenotypes in Patients With Schizophrenia or Psychotic Bipolar Disorder and Their Relatives
Pawel Skudlarski, Ph.D.; David J. Schretlen, Ph.D.; Gunvant K. Thaker, M.D.; Michael C. Stevens, Ph.D.; Matcheri S. Keshavan, M.D.; John A. Sweeney, Ph.D.; Carol A. Tamminga, M.D.; Brett A. Clementz, Ph.D.; Kasey O’Neil, B.Sc.; Godfrey D. Pearlson, M.D.
Am J Psychiatry 2013;170:886-898. doi:10.1176/appi.ajp.2013.12111448
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Dr. Sweeney reports receiving study drugs from Janssen and Seaside and serving on advisory boards of Takeda, Bristol-Myers Squibb, Pfizer, Roche, and Eli Lilly. Dr. Keshavan reports receiving grants from GlaxoSmithKline and Sunovion. Dr. Pearlson reports serving on a Bristol-Myers Squibb advisory panel. Disclosures for Dr. Tamminga, as a Deputy Editor of the American Journal of Psychiatry, were published in the January issue. The other authors report no financial relationships with commercial interests.

Funded by NIMH grants R37 MH-43375 and R01 MH-074797 to Dr. Pearlson, von Humboldt Foundation funding and NIMH grant MH-077862 to Dr. Sweeney, NIMH grant MH-78113 to Dr. Keshavan, NIMH grant MH-077851 to Dr. Tamminga, and NIMH grant R01 MH-077945 to Dr. Thaker.

From the Olin Neuropsychiatry Research Center, Hartford Hospital/Institute of Living, Hartford, Conn.; the Departments of Psychiatry and Neurobiology, Yale School of Medicine, New Haven, Conn.; the Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore; the Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore; the Beth Israel and Deaconess Medical Center, Harvard Medical School, Boston; the Department of Psychiatry, University of Texas Southwestern, Dallas; and the Departments of Psychology and Neuroscience, Bioimaging Research Center, University of Georgia, Athens, Ga.

Address correspondence to Dr. Skudlarski (pawel.skudlarski@yale.edu).

Copyright © 2013 by the American Psychiatric Association

Received November 21, 2012; Revised January 18, 2013; Accepted February 04, 2013.

Abstract

Objective  Both schizophrenia and bipolar disorder are hypothesized to involve disordered brain connectivity. Prior studies show low white matter integrity, measured with diffusion tensor imaging, for both disorders. The authors studied disease specificity and endophenotypic status of these abnormalities by examining patients and their unaffected relatives.

Method  The 513 participants included probands with schizophrenia, probands with psychotic bipolar disorder, their first-degree relatives, and healthy comparison subjects. Fractional anisotropy measures of white matter integrity were collected at two sites as a part of the Bipolar-Schizophrenia Network on Intermediate Phenotypes project. Relatives with cluster A or B personality characteristics were further examined.

Results  Both the probands with schizophrenia and those with psychotic bipolar disorder showed lower fractional anisotropy than the comparison subjects in multiple white matter regions; differences were more marked in schizophrenia. No significant differences existed between proband groups, but in some brain regions scores on a measure of the dimensional continuum between schizophrenia and bipolar disorder, the Schizo-Bipolar Scale, showed correlations with fractional anisotropy. Many regions affected in schizophrenia probands showed similar but smaller effects in relatives, with a continuous fractional anisotropy decrease from healthy subjects to relatives to cluster A/B relatives to probands. The pattern for psychotic bipolar disorder was similar but involved fewer brain regions. Effects in bipolar relatives were limited to younger subjects. Fractional anisotropy decreased with age in all groups; this decrease was exaggerated in schizophrenia but not psychotic bipolar disorder.

Conclusions  Fractional anisotropy was highly heritable, supporting its value as a potential endophenotype.

Abstract Teaser
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FIGURE 1. Differences in Fractional Anisotropy Between Healthy Comparison Subjects, Probands With Schizophrenia or Psychotic Bipolar Disorder, and Probands’ Relatives

a Results are from voxel-based randomized analysis. Orange voxels show lower fractional anisotropy in both schizophrenia and bipolar probands, red in schizophrenia probands only (p<0.01, whole-brain correction by threshold-free cluster enhancement). Yellow voxels show lower fractional anisotropy both in schizophrenia and bipolar probands and in unaffected relatives of schizophrenia probands (p<0.05, corrected).

b Regions were anatomically predefined. Red and yellow show regions (right anterior corona radiata, superior aspect, and left anterior corona radiata) where schizophrenia relatives differ significantly from comparison subjects (resemble probands). Violet shows regions where fractional anisotropy of relatives is significantly higher than that of probands (thus resembles value of comparison subjects).

c Voxels show regression of fractional anisotropy values to the clinical score (0, healthy comparison subjects; 1, unaffected relatives; 2, relatives with cluster A personality traits; 3, probands) significant at p<0.01 after whole-brain correction by threshold-free cluster enhancement. Yellow regions show differences for both schizophrenia and psychotic bipolar disorder; orange voxels show significant differences in schizophrenia only.

FIGURE 2. Fractional Anisotropy Values for Anatomically Defined Genu of Corpus Callosum in Healthy Comparison Subjects, Probands With Schizophrenia or Psychotic Bipolar Disorder, and Probands’ Relatives

FIGURE 3. Regions With Significant Heritability of Average Fractional Anisotropy in Healthy Comparison Subjects, Probands With Schizophrenia or Psychotic Bipolar Disorder, and Probands’ Relativesa

a Significant at p<0.05 corrected for multiple comparisons.

Anchor for Jump
TABLE 1.Characteristics of Healthy Comparison Subjects, Probands With Schizophrenia or Psychotic Bipolar Disorder, and Probands’ Relatives
Table Footer Note

a Met the criteria for an axis II cluster A or B disorder or possessed one fewer criteria than required for the diagnosis.

Table Footer Note

b Significant difference (p<0.05) from value for comparison group (two-tailed t test).

Anchor for Jump
TABLE 2.Analysis of Fractional Anisotropy in Brain Regions of Interest in Healthy Comparison Subjects, Probands With Schizophrenia or Psychotic Bipolar Disorder, and Probands’ Relatives
Table Footer Note

a The only regions included are the 29 (out of a total of 76) that showed effects in voxel-based analysis with threshold-free cluster enhancement and that showed significant differences in fractional anisotropy values between the probands with schizophrenia and the healthy comparison subjects.

Table Footer Note

b Including three meta-analysis articles showing fractional anisotropy findings in schizophrenia and eight articles showing differences in fractional anisotropy in bipolar disorder.

Table Footer Note

c Performed on smaller regions centered at the maxima found in the primary analyses. The smaller regions defined by the comparison of the healthy subjects and probands were interrogated for the effects seen in the relatives.

Table Footer Note

d Relatives with cluster A or B traits met the criteria for an axis II cluster A or B disorder or possessed one fewer criteria than required for the diagnosis.

Table Footer Note

e Significant (p<0.01) as shown by mean fractional anisotropy values for whole, anatomically defined regions, not focused subregions.

Table Footer Note

f Significant clinical regression effect, i.e., decrease in severity from probands to relatives with cluster A or B symptoms to other relatives to healthy comparison subjects.

Table Footer Note

g p<0.05/76 (correction for multiple comparisons).

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