The Effect of Antipsychotic Treatment on Cortical Gray Matter Changes in Schizophrenia: Does the Class Matter?

Important finding from MRI studies done in Schizophrenia:
Reduction in whole-brain and gray matter (GM) volumes were associated with higher exposure to antipsychotics. (Schizophr Bull 39:1129–1138; Arch Gen Psychiatry 68:128–137)

However, these studies and meta-analysis did not analyze the potential impact of first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) on progressive loss of brain tissue.

In this Meta-analysis and Meta-regression article published in Biological Psychiatry, they reported the results of a meta-analysis of MRI longitudinal studies analyzing cortical GM volume in schizophrenia specifically aimed at investigating:
1) the influence of antipsychotic medications on changes in GM volume over time;
2) the possible different impact of SGAs versus FGAs on such changes; and
3) the influence of other potential moderators of longitudinal changes in cortical brain volumes.

Results of Meta-analysis and Meta-regression:
- No previous quantitative review tried to analyze separately the effects of FGAs and SGAs on cortical GM changes.
- Longitudinal changes in whole-brain cortical GM volume in schizophrenia are related to exposure to antipsychotic medication during the MRI follow-up.
Whole-Brain GM Volume Reduction:
- In patients treated with FGAs or mixed treatments: whole-brain GM volume reduction was inversely correlated with exposure to antipsychotic treatment.
- In patients treated with SGAs: the cumulative exposure to antipsychotics did not correlate with GM volume changes over time and was not associated with cortical tissue loss.
Mean Daily Dose (MDD) of antipsychotics:
- In patients treated with FGAs or mixed treatments: Significant negative correlation emerged- higher MDD of antipsychotics associated with higher reduction of whole brain GM volume over time.
- In patients treated with SGAs: Significant positive correlation seen- higher MDD of antipsychotics associated with lower reduction of whole brain GM volume over time.

Authors explains above findings by this hypothesis that:
SGAs may have a neuroprotective effect either by:
* increasing the expression of neurotrophic factors or
* stimulating neurogenesis or
* increasing the activity of NMDA glutamate receptors.
Excessive reduction in cortical GM observed with FGAs may be due to:
* direct neurotoxic effect secondary to oxidative stress and/or excitotoxic phenomenon.