What is happening in the brain during schizophrenia?

Neuroimaging reveals loss of brain gray matter volume in schizophrenia. New insights into the location and progression of these brain changes, their relationship to the normal aging brain and significance, and how they are impacted by first- and second-generation antipsychotic therapy were presented by experts in a fascinating state-of-the-art symposium at WCP 2021.

Location of cortical gray matter changes

Reduction in gray matter volume is most prominent and more widespread in the early phases of schizophrenia

Many neuroimaging studies have confirmed progressive reduction in cortical gray matter volume in schizophrenia, said Professor Antonio Vita, Brescia, Italy. These changes are not widespread but confined to specific areas of the brain. Their location was demonstrated by a meta-analysis and meta-regression carried out by Professor Vita and his colleagues,1 which showed:

  • Reduction in gray matter volume is most prominent and more widespread in the early phases of schizophrenia, affecting frontal, temporal and parietal gray matter4
  • Reduction in total gray matter volume over time is most noticeable in the left hemisphere and superior temporal regions1

As schizophrenia progresses, the reduction in gray matter volume is most noticeable in the left hemisphere and superior temporal regions

Among individuals with first-episode schizophrenia, progression of gray matter changes has been shown to be restricted to those with a poor outcome,2 noted Professor Vita.


Changes in the brain before transition to psychosis

The changes in the brain precede the transition to psychosis before treatment with antipsychotics, said Professor Lynn DeLisi, Boston, MA, who highlighted a review and meta-analysis of neuroanatomical correlates of clinical high-risk (CHR) for psychosis and potential predictors of transition.

Less cortical gray matter in certain brain regions in individuals who transition to psychosis

Among individuals with CHR for psychosis, transition to psychosis was associated with less cortical gray matter in the right temporal lobe, anterior cingulate and paracingulate.3

Structural magnetic resonance images have also revealed neurobiologically distinct subgroups of patients with schizophrenia, and this has been useful for individualizing interventions,4 said Professor DeLisi. But it is not clear what the interventions should be or when they should be applied. The challenge for the next decades is to develop interventions that prevent the progressive brain changes.


Effects of antipsychotic therapy and normal aging on brain volume loss

Higher mean daily antipsychotic intake in patients treated only with second-generation antipsychotics is linked to less progressive gray matter loss

Confounders of excessive brain volume loss during schizophrenia include first-generation vs second-generation antipsychotic therapy and normal aging, said Professor Vita.

Cumulative antipsychotic intake with at least one first-generation antipsychotic is linked to a significantly higher loss of total cortical gray matter volume over time in patients with schizophrenia compared with healthy controls,5 he explained.

In contrast, higher mean daily antipsychotic intake in patients treated only with second-generation antipsychotics was linked to less progressive gray matter loss.6

Use of second-generation antipsychotics might prevent or slow the progressive brain changes

In terms of brain aging, brain age at the onset of schizophrenia is significantly greater than chronological age (+3.36 years).7 This difference between chronological age and schizophrenia brain age is called “schizophrenia brain age gap”, said Professor Vita. It progressively increases during follow-up, but by approximately 5 years after illness onset, the acceleration decreases from 2.5 years/year just after illness onset to about the normal rate (1 year/year).7

Interventions that might prevent or slow progressive brain changes in schizophrenia include early intervention, continuity of treatment, prevention of relapses and use of second-generation antipsychotics, concluded Professor Vita.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.


  1. Vita A, et al. Progressive loss of cortical gray matter in schizophrenia: a meta-analysis and meta-regression of longitudinal MRI studies. Transl Psychiatry 2012;2(11):e190.
  2. Rosa PGP, et al. What determines continuing grey matter changes in first-episode schizophrenia and affective psychosis? Psychol Med 2015;45(4):817–828.
  3. Fortea A, et al. Cortical gray matter reduction precedes transition to psychosis in individuals at clinical high-risk for psychosis: A voxel-based meta-analysis. Schizophr Res 2021;232:98–106.
  4. Xiao Y, et al. Subtyping schizophrenia patients based on patternsof structural brain alterations. Schizophr Bull 2021 Sep 11;sbab110.doi: 10.1093/schbul/sbab110.
  5. Roiz-Santiañez R, et al. Brain structural effects of antipsychotic treatment in schizophrenia: a systematic review. Current Neuropharmacol 2015;13:422–34.
  6. Vita A, et al. The effect of antipsychotic treatment on cortical gray matter changes in schizophrenia: does the class matter? A meta-analysis and meta-regression of longitudinal magnetic resonance imaging studies. Biol Psychiatry 2015;78(6):403–12.
  7. Schnack H, et al. Accelerated brain aging in schizophrenia: a longitudinal pattern recognition study. Am J Psychiatry 2016;173(6):607–16.