Why antipsychotics need time to kick in

Insight into how drugs work may explain the delayed action of medications for schizophrenia

New details about how some drugs for schizophrenia accumulate in the brain may help explain why patients often must wait for weeks for the medications to work.

Because many commonly used antipsychotics such as haloperidol and clozapine quickly latch onto their targets, it would seem that the drugs should bring fast relief.

“But there’s always a side story,” says neuroscientist Michael Cousin of the University of Edinburgh in Scotland. “There’s another layer of complexity.”

Researchers led by Teja Groemer of Friedrich-Alexander University of Erlangen-Nürnberg in Germany illuminate this process in the June 7 Neuron by describing how the buildup of certain drugs in the brain may have underappreciated consequences for their effectiveness.

The idea that drugs accumulate in the brain isn’t totally new; other scientists have suggested that antipsychotic drugs can pile up in certain places, Groemer says. But most people have assumed such accumulation is inconsequential.

Not so, Groemer and his team found. Stockpiled drugs may actually squelch nerve cells’ behavior in a highly selective way by being released only when needed most.

Using a proxy compound that could be seen with a microscope (because making the drugs themselves visible would have changed their behavior), the researchers watched the chemical build up in small pockets, called synaptic vesicles, inside nerve cells that were growing in a dish. Normally, these vesicles’ cargo is cell-manufactured molecular messages. In an excited nerve cell, vesicles rise to the surface, glob on to the cell’s outer membrane and float their messages out and away.

Vesicles chock full of unnatural cargo — haloperidol, chlorpromazine, clozapine and risperidone — also dump their contents into the space between nerve cells when a cell is excited, the team found. This evacuation sends a “calm down” signal back to the cell that releases the drug. In this way, the activity of a nerve cell dictates the drugs’ effects. The more active a cell, the more antipsychotic drug it gets. “The brain doses itself,” Groemer says.

This accumulation process might help explain why people typically have to take such drugs for several weeks before noticeably improving: The drugs need time to accumulate in the vesicles before exerting their calming effect. Other drugs with similar chemical makeups, including some antidepressants, may behave similarly.

The experiments were conducted with cells in dishes and with rodents; it’s not clear whether the same thing happens in people. If so, the results could have important implications for doctors, Groemer says. “One really needs to wait for a drug to accumulate before deciding whether the drug is effective or not.”

Laura Sanders is the neuroscience writer. She holds a Ph.D. in molecular biology from the University of Southern California.

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