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A schizophrenia drug turns on protein factories in cells

Haloperidol reshapes neurons, which might explain how the medicine works

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An antipsychotic drug may banish hallucinations and delusions by prompting neurons to churn out proteins that reshape the cells, a new study suggests. The results, published in the January 14 Science Signaling, may help scientists develop better psychiatric drugs, and might explain what goes wrong in some mental disorders.

Since the 1950s, haloperidol has been prescribed to quiet the debilitating symptoms that mark schizophrenia. Despite its long history, scientists still don’t know how the drug works, or why it starts to relieve symptoms within hours but takes weeks to fully work. 

Haloperidol kicks off a cellular chain reaction that ultimately leads to changes in neuron shapes, neuroscientist Eric Klann of New York University and colleagues found. Haloperidol initiates a series of biochemical events that enables the protein mTORC1 to turn on the production of a flurry of new proteins.

Klann and his colleagues treated rat brain cells in a dish with haloperidol. After just five hours, the neurons started to produce proteins that signal the start of a productivity burst. “The system is being ramped up so it can make more proteins,” Klann says.

Some of the next wave of proteins, which showed up at 48 hours, had specialized jobs: They were tasked with reshaping neurons, changes that might make the cells better able to send and receive messages, the team found. This neuron remodeling might be a necessary step toward other important and time-consuming changes, Klann says.

The team doesn’t know how persistent the protein and neuron shape changes are, but they’re probably not permanent. Once patients stop taking haloperidol, their symptoms can return, Klann says.

The results raise the possibility of developing new schizophrenia drugs that selectively change the rates of mTORC1-directed protein production, says neuroscientist Argel Aguilar-Valles of McGill University in Montreal. More-targeted drugs might work without some of haloperidol’s side effects, which include severe muscle stiffness and trembling.

Beyond explaining how haloperidol works, the results hint that abnormal protein production might be at the heart of schizophrenia and other psychiatric disorders, says neuroscientist Raymond Kelleher of Harvard Medical School. Studies suggest that protein production controlled by mTORC1 is faulty in autism and Fragile X syndrome, a genetic disorder marked by intellectual disability.

Similar processes might underlie severe depression. Like haloperidol, an experimental, fast-acting antidepressant called ketamine changes neurons’ protein production. 

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