Antipsychotics come from a long line of accidents. In 1876, German chemists created a textile dye called methylene blue, which happened to also dye cells. It meandered into biology labs and, soon after, proved lethal against malaria parasites. Methylene blue became modern medicine’s first fully synthetic drug, lucking into gigs as an antiseptic and an antidote for carbon monoxide poisoning. Cue the spinoffs: A similar molecule, promethazine, became an antihistamine, sedative, and anesthetic. Other phenothiazines followed suit. Then, in 1952, came chlorpromazine.
After doctors sedated a manic patient for surgery, they noticed that chlorpromazine suppressed his mania. A series of clinical trials confirmed that the drug treated manic symptoms, as well as hallucinations and delusions common in psychoses like schizophrenia. The US Food and Drug Administration approved chlorpromazine in 1954. Forty different antipsychotics sprang up within 20 years. “They were discovered serendipitously,” says Jones Parker, a neuroscientist at Northwestern University. “So we don't know what they actually do to the brain.”
But Parker really wants to know. He has spent his career studying brains flooded with dopamine, the condition that underpins psychosis. And while he doesn’t pretend to fully understand antipsychotics either, he believes he’s got the right approach to the job: gazing directly into brains. With a combination of tiny lenses, microscopes, cameras, and fluorescent molecules, Parker’s lab can observe thousands of individual neurons in mice, in real time, as they experience different antipsychotic drugs. That’s now paying dividends. In results appearing in the August issue of Nature Neuroscience, Parker shows that an assumption about antipsychotics that’s almost as old as the drugs themselves is …. well, wrong.
Neuroscientists have long thought that antipsychotics dampen extreme dopamine transmission by sticking to receptors in a type of cell called spiny projection neurons, or SPNs. The drugs basically box out the dopamine at receptor proteins called D1 or D2 (where “D” stands for dopamine). Each of the spiny neurons sport either D1 or D2—they’re genetically distinct. Experiments on calf brain extracts in the 1970s showed that the most powerful antipsychotics are the ones that cling strongly to the D2 SPNs in particular, so decades worth of antipsychotics were designed and refined with D2 in mind.
But when Parker’s team probed how four antipsychotics affect D1, D2, and mouse behavior, they found that the most drug interaction is actually happening at D1 neurons. “It’s good to start with a logical prediction and then let the brain surprise you,” Parker says.
The notion that D1 receptors may be a more important target upends decades of research in a $15 billion market for drugs that are famously erratic. Antipsychotics don’t work for about 30 percent of people who try them. They’re plagued by side effects, from extreme lethargy to unwanted facial movements, and rarely address the cognitive symptoms of psychosis, like social withdrawal and poor working memory.
Assumptions about D2 ran deep, says Katharina Schmack, a psychiatrist and neuroscientist who was not involved in the work and studies psychosis at the Francis Crick Institute in the United Kingdom: “This was the textbook knowledge.”