Hypothalamic Abnormalities in Schizophrenia: Sex Effects and Genetic Vulnerability

Background: This is a unique hypothalamic magnetic resonance imaging (MRI) study in schizophrenia, an important region in the limbic system. We hypothesized abnormal volumetric increases, with greater severity in multiplex families (more than one ill member) compared with simplex families (one ill). We tested the hypothesis that normal hypothalamic sexual dimorphism is disrupted in schizophrenia. Methods: Eighty-eight DSM-III-R schizophrenia cases (40 simplex and 48 multiplex), 43 first-degree nonpsychotic relatives, and 48 normal comparisons systematically were compared. A 1.5-Tesla General Electric scanner was used to acquire structural MRI scans, and contiguous 3.1-mm slices were used to segment anterior and posterior hypothalamus. General linear model for correlated data and generalized estimating equations were used to compare cases, relatives, and controls on right and left hypothalamus, controlled for age, sex, and total cerebral volume. Spearman's correlations of hypothalamic volumes with anxiety were calculated to begin to examine arousal correlates with structural abnormalities. Results: Findings demonstrated significantly increased hypothalamic volume in cases and nonpsychotic relatives, particularly in regions of paraventricular and mammillary body nuclei, respectively. This increase was linear from simplex to multiplex cases, was positively correlated with anxiety, and had a greater propensity in women. Conclusions: Findings suggest important implications for understanding genetic vulnerability of schizophrenia and the high rate of endocrine abnormalities.