Why do antipsychotics take time to kick in? Protein synthesis may be one explanation.

Acute antipsychotic treatment increases Akt-mTORC1 pathway signaling in D2R-positive
neurons.
[Image courtesy of Science Signaling/AAAS]

Antipsychotic drugs have been used clinically since the 1970s to treat neurological disorders such as schizophrenia and bipolar disorder. But researchers have noted that it takes three or more weeks before the drugs are fully effective.

To figure out the underlying reason for this time lag, a team led by Eric Klann and Moses Chao at New York University analyzed neurons in culture as well as in live mice to see what happened at the molecular level when neurons were exposed antipsychotic drugs. They studied a drug called haloperidol, a first-generation drug for schizophrenia, because previous studies had shown that the drug acts on the kinase Akt. It just so happened, explains Klann, that his and Chao’s laboratories have a longstanding interest in an Akt pathway that involves a protein complex called mTORC1. This Akt-mTORC1 pathway is important for protein synthesis. 

The investigators demonstrated that Akt became activated and turned on mTORC1 when haloperidol was given to neurons. The activation of this pathway led to increased protein synthesis. The cells made more proteins involved in mRNA translation, which was followed by production of more cytoskeletal proteins. The neurons also appeared to become morphologically more complex when exposed to haloperidol, such as creating more branches to make more connections with other neurons. Klann says some of the proteins that they found “were also reported as being altered in the brains of both (autopsied) rodents and human patients treated chronically with antipsychotics.”

The investigators say that their work raises some new questions. One of them is “whether or not chronic administration of haloperidol would maintain the morphological complexity or if this is an initial response that declines over time,” says Klann. He adds that he hopes that the work eventually will lead to the development of biomarkers that accurately track the effectiveness of antipsychotics as well as better drugs.