Duration of untreated psychosis is associated with orbital-frontal grey matter volume reductions in first episode psychosis

Schizophr Res. 2011 Jan;125(1):13-20. doi: 10.1016/j.schres.2010.09.021. Epub 2010 Nov 6.


Background: Delay in treatment of psychosis is associated with poor clinical and social outcome and is measured as the duration of untreated psychosis (DUP) prior to treatment of the first episode. It has been suggested that this may be mediated through toxic effects of psychosis on the structure and function of the brain. Equivocal evidence exists regarding association between longer DUP and neuro-anatomical changes such as, reduced grey matter volume in specific regions in the brain and deficits in neurocognitive functions.

Objective: To examine if duration of untreated psychosis (DUP) preceding treatment of a first episode of psychosis is associated with structural brain abnormalities and deficits in neurocognitive functions.

Method: We investigated the relationship between DUP and grey matter volume using voxel-based morphometry techniques and with multiple domains of cognition. Eighty patients with a first episode of psychosis were separated into two equal sized groups based on a median split (18 weeks) of their DUP.

Results: Compared to the short-DUP group (mean DUP 7.9 weeks ± 5.6), the long-DUP group (mean 113.7 weeks ± 170 .4) showed significant grey matter volume reductions in orbital-frontal regions (bilateral medial frontal gyrus and bilateral rectal gyrus, BA 11) and parietal regions (postcentral gyrus and superior parietal lobule) as well as a significant reduction in whole brain grey matter volume (p<0.04). For schizophrenia spectrum cases only these findings were confined to left rectal gyrus. There were no differences in white matter or cerebral spinal fluid volumes or on cognitive functions. Results are controlled for antipsychotic medication exposure.

Limitations: The inherent difficulty in separating slow and insidious onset from long-DUP may limit the interpretation of our results and there may be an overlap between DUP and duration of illness (including the prodrome).

Conclusion: Patients with a longer delay in treatment of psychosis show a significant reduction in overall grey matter volume with specific reductions in the inferior-orbital region. These results provide some support to a possible neurotoxic effect of prolonged untreated psychosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antipyretics / therapeutic use
  • Behavioral Symptoms / etiology
  • Behavioral Symptoms / pathology
  • Brain Mapping
  • Cognition Disorders / etiology
  • Cognition Disorders / pathology
  • Female
  • Humans
  • Magnetic Resonance Imaging / methods
  • Male
  • Neuropsychological Tests
  • Prefrontal Cortex / pathology*
  • Psychotic Disorders / complications
  • Psychotic Disorders / drug therapy
  • Psychotic Disorders / pathology*
  • Schizophrenia / complications
  • Schizophrenia / pathology*
  • Time Factors
  • Young Adult


  • Antipyretics