Atypical Antipsychotics Work Against Themselves at a Genetic Level

Mechanisms of antipsychotic drugs are more complex than previously thought.

In schizophrenia, presumed therapeutic actions of atypical antipsychotics (AAs) include antagonism of dopamine D₂ and 5-HT_2A receptors. Investigators receiving some industry support examined AAs' effects on the metabotropic glutamate 2 receptor (mGlu2) in mouse and postmortem human studies.

Chronic clozapine and risperidone (but not haloperidol or fluoxetine) decreased histone acetylation at the promoter, thus down-regulating mGlu2 expression in frontal cortex. Compared with controls, schizophrenia patients treated with AAs (but not untreated patients) showed higher frontal-cortex expression of histone deacetylase 2 (HDAC2), which represses gene expression by altering chromatin structure. Antagonism of the 5-HT_2A receptor increased HDAC2 exp…

Reviewing Author

Steven Dubovsky, MD

Disclosures

Grant/Research SupportTower Foundation; Patrick Lee Foundation; Boehringer Ingelheim; Intra-Cellular Therapies; Janssen; Biogen; Allergan

Editorial BoardsMind and Brain; Bulletin of the Menninger Clinic; Current Psychiatry; Journal of Psychosomatic Research

Steven Dubovsky, MD

Disclosures

Grant/Research SupportTower Foundation; Patrick Lee Foundation; Boehringer Ingelheim; Intra-Cellular Therapies; Janssen; Biogen; Allergan

Editorial BoardsMind and Brain; Bulletin of the Menninger Clinic; Current Psychiatry; Journal of Psychosomatic Research