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

Schizophr Res. 2011 Sep;131(1-3):139-45. doi: 10.1016/j.schres.2011.05.006. Epub 2011 Jun 8.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 1-Pyrroline-5-Carboxylate Dehydrogenase / deficiency
  • Adolescent
  • Adult
  • Aged
  • Amino Acid Metabolism, Inborn Errors / blood*
  • Amino Acid Metabolism, Inborn Errors / complications*
  • Amino Acid Metabolism, Inborn Errors / drug therapy
  • Analysis of Variance
  • Brief Psychiatric Rating Scale
  • Case-Control Studies
  • Chi-Square Distribution
  • Cross-Sectional Studies
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Humans
  • Male
  • Middle Aged
  • Proline / blood*
  • Proline Oxidase / blood
  • Proline Oxidase / deficiency
  • Schizophrenia / blood*
  • Schizophrenia / complications*
  • Schizophrenia / drug therapy
  • Valproic Acid / therapeutic use
  • Young Adult


  • Enzyme Inhibitors
  • Valproic Acid
  • Proline
  • 1-Pyrroline-5-Carboxylate Dehydrogenase
  • Proline Oxidase

Supplementary concepts

  • Hyperprolinemia type 2