Antipsychotics May Contribute to Gray Matter Loss in Schizophrenia

Second-generation antipsychotics appear to have a neuroprotective effect on the brain.

Antipsychotic medications are a necessity for patients with schizophrenia who wish to lessen their degree of functional disability in their day to day lives. However, new research indicates that some drugs meant to treat the disorder may also promote brain degeneration.

Previous research has indicated through cross-sectional and longitudinal MRI that those with schizophrenia experience progressive structural brain abnormalities associated with the duration and cumulative intake of antipsychotic treatments. However, how different classes of drugs affect brain structure and function is not known.

Researchers from the University of Brescia in Brescia, Italy compiled data from 18 imaging studies in order to evaluate the effects of first- and second-generation antipsychotics on gray matter in 1,155 patients with schizophrenia and 911 healthy controls.

As expected, patients with schizophrenia had a significantly higher loss of total cortical gray matter volume compared to controls over time, with the loss related to cumulative antipsychotic intake during the interval between imaging scans. When comparing first- and second-generation antipsychotics, researchers found a moderate role of medication intake on gray matter changes, with more progressive gray matter volume loss linked to higher intake of at least one first-generation antipsychotic, and less progressive gray matter volume loss with higher daily intake of only second-generation antipsychotics.

The data indicates that second-generation antipsychotics may be neuroprotective; a result that has been replicated in several animal studies and few clinical studies. Still, many questions about the long-term effects of antipsychotics on the brain remain.

“Although this is a clinically meaningful result, many issues remain to be clarified: for instance, we still do not know whether the effects on the brain of antipsychotics vary as a function of age and stage of illness, or whether they may occur only when a certain threshold of exposure (daily dose or cumulative dose) is reached,” said researcher Antonio Vita, MD, PhD.

“Clarification of these issues will have crucial importance in the clinical management of schizophrenia and will allow a better understanding of the mechanisms underlying the progression of structural brain abnormalities in the disease.”


  1. Vita A et al. Biol Psychiatry. 2015; doi:10.1016/j.biopsych.2015.02.008.