Evidence for association of hyperprolinemia with schizophrenia and a measure of clinical outcome

Abstract

There are multiple genetic links between schizophrenia and a deficit of proline dehydrogenase (PRODH) enzyme activity. However, reports testing for an association of schizophrenia with the resulting proline elevation have been conflicting. The objectives of this study were to investigate whether hyperprolinemia is associated with schizophrenia, and to measure the relationship between plasma proline, and clinical features and symptoms of schizophrenia. We performed a cross-sectional case-control study, comparing fasting plasma proline in 90 control subjects and 64 schizophrenic patients and testing for association of mild to moderate hyperprolinemia with schizophrenia. As secondary analyses, the relationship between hyperprolinemia and five measures of clinical onset, symptoms and outcome were investigated. Patients had significantly higher plasma proline than matched controls (p<0.0001), and categorical analysis of gender adjusted hyperprolinemia showed a significant association with schizophrenia (OR 6.15, p=0.0003). Hyperprolinemic patients were significantly older at their first hospitalization (p=0.015 following correction for multiple testing). While plasma proline level was not related to total, positive or negative symptoms, hyperprolinemic status had a significant effect on length of hospital stay (p=0.005), following adjustment for race, BPRS score, and cross-sectional time from admission to proline measurement. Mild to moderate hyperprolinemia is a significant risk factor for schizophrenia, and may represent an intermediate phenotype in the disease. Hyperprolinemic patients have a significantly later age of first psychiatric hospitalization, suggestive of later onset, and hospital stays 46% longer than non-hyperprolinemic subjects. These findings have implications in the etiology of schizophrenia, and for the clinical management of these patients.

Figure 1. Hyperprolinemia in Schizophrenia, and the Effect on Age at First Hospitalization (AFH) and Length of Hospital Stay (LOHS)

1a Fasting Plasma Proline in SZ and Control Groups. The boxplot illustrates the significant difference between control (174.28±55.97) and SZ patient (215.84± 63.00) groups, Mann-Whitney z=−4.58, p<0.0001. 1b. Bivariate Relationship Between AFH and Hyperprolinemia. Hyperprolinemic SZ patients have a significantly later age of first hospitalization (29.9±10.2 years) compared to non-hyperprolinemic patients (22.2±5.4 years), log-normal model: z=3.37, 1df, p=0.001. Age at first hospitalization could not be determined for 17 subjects. 1c) Bivariate Relationship Between LOHS and Hyperprolinemia. The duration of their hospital stay is longer for hyperprolinemic SZ patients (47.0±19.7 days), compared to non-hyperprolinemic patients (30.1±21.9 days), gamma-log model: z=2.38, 1df, p=0.017. 19 subjects were excluded from analysis because they were transferred or discharged to another treatment facility. A gamma-log model showed no effect of AFH on LOHS for all 35 subjects for whom AFH could be determined and who were not transferred to a second care facility (z=1.35, 1df, p=0.178), or for the subset of 9 hyperprolinemic subjects (z=1.04, 1df, p=0.298). Key: SZ: Schizophrenia, NH: Non-hyperprolinemic, H: Hyperprolinemic, AFH: Age at first hospitalization, LOHS: length of hospital stay, IQR: interquartile range. Red jittered points represent individual subject data. The horizontal line within each box represents the group mean (mean ± SD reported). The box indicates the IQR. The whiskers extend to the most extreme data point which is <1.5 times the IQR.