Progressive structural brain abnormalities and their relationship to clinical outcome: a longitudinal magnetic resonance imaging study early in schizophrenia

Arch Gen Psychiatry. 2003 Jun;60(6):585-94. doi: 10.1001/archpsyc.60.6.585.


Background: Many studies have shown that structural brain abnormalities in schizophrenia are already present by the time of index evaluation of first-episode patients. However, whether these abnormalities progressively worsen during the subsequent course of the disorder remains unresolved.

Methods: To study the longitudinal progression of structural brain abnormalities, high-resolution multispectral magnetic resonance images obtained on 73 recent-onset schizophrenic patients and 23 controls were analyzed using state-of-the-art, well-validated, and highly reliable neuroimaging tools. The mean duration between initial and follow-up MRIs was 3 years. Repeated-measures analysis of covariance was carried out to determine (1) whether brain volume changes differed between patients and controls and (2) the significance of regional brain changes on functional outcome in schizophrenia.

Results: We found accelerated enlargement in cortical sulcal cerebrospinal fluid spaces early in the course of schizophrenia. Instead of the usual trajectory of volume enlargement, patients showed progressive reduction in frontal lobe white matter volume. A reciprocal increase in frontal lobe cerebrospinal fluid volume also occurred at a more rapid rate in patients than in controls. In keeping with most of our a priori hypotheses, patients with poor outcome had greater lateral ventricular enlargement over time than patients with good outcome. Progressive decrement in frontal lobe white matter volume and enlargement in frontal lobe cerebrospinal fluid volume were associated with greater negative symptom severity. Reductions in frontal lobe gray and white matter volumes correlated with poorer executive functioning.

Conclusions: There are ongoing changes in the brains of schizophrenic patients during the initial years after diagnosis despite ongoing antipsychotic drug treatment. These progressive changes seem to be most evident in the frontal lobes and to correlate with functional impairment. Disruptions in neurodevelopment or neural plasticity may act alone or in combination to bring about these progressive brain deficits in schizophrenia.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Age of Onset
  • Antipsychotic Agents / pharmacology
  • Antipsychotic Agents / therapeutic use
  • Brain / anatomy & histology*
  • Brain / drug effects
  • Brain / growth & development
  • Cerebral Ventricles / anatomy & histology
  • Cerebral Ventricles / drug effects
  • Cerebral Ventricles / growth & development
  • Disease Progression
  • Female
  • Follow-Up Studies
  • Frontal Lobe / anatomy & histology
  • Frontal Lobe / drug effects
  • Frontal Lobe / growth & development
  • Humans
  • Longitudinal Studies
  • Magnetic Resonance Imaging / statistics & numerical data
  • Male
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology
  • Outcome Assessment, Health Care
  • Schizophrenia / diagnosis*
  • Schizophrenia / drug therapy
  • Temporal Lobe / anatomy & histology
  • Temporal Lobe / drug effects
  • Temporal Lobe / growth & development


  • Antipsychotic Agents