We were wrong about antipsychotics

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Antipsychotics exist thanks to a long series of accidents . In 1876, German chemists created a fabric dye that also dyed cells called methylene blue. It sneaked into biology laboratories and, soon after, proved lethal against malaria parasites. Methylene blue became the first fully synthetic drug in modern medicine and was used as an antiseptic and antidote to carbon monoxide poisoning. Then the referrals began; a similar molecule, promethazine, became an antihistamine, sedative, and anesthetic. Other phenothiazines followed. In 1952, chlorpromazine appeared.

After sedating a manic patient for surgery, doctors observed that chlorp Phone Number List romazine suppressed his mania . A series of clinical trials confirmed that the drug treated manic symptoms, as well as the hallucinations and delusions common in psychoses such as schizophrenia . The US Food and Drug Administration (FAA) approved chlorpromazine in 1954. In the 20-year period, 40 different antipsychotics emerged. "They were discovered by chance," says Jones Parker, a neuroscientist at Northwestern University. "So we don't know what they actually do in the brain," he confesses.

How do antipsychotics work on the brain?
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 claim to fully understand antipsychotics either, he believes he has the right approach for the job: looking directly inside brains . Using 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. This is paying off. The results appear in the August issue of Nature Neuroscience. Parker demonstrates there that there is something we thought about antipsychotics that was, well, wrong.

Neuroscientists have long thought that antipsychotics dampen extreme dopamine transmission by latching onto receptors on a type of cells called spiny projection neurons , or SPNs. The drugs basically encase dopamine in receptor proteins called D1 or D2, where "D" stands for dopamine. Each of the spiny neurons has D1 or D2 proteins that are genetically distinct. Experiments conducted in the 1970s with calf brain extracts demonstrated that the most potent antipsychotics are those that bind strongly to D2 SPNs in particular. Therefore, for decades antipsychotics were designed and perfected taking D2 into account.



But when Parker's team investigated how four antipsychotics affect the D1, D2 neurons and the behavior of the mice themselves, they discovered that the greatest interaction between drugs occurs in the D1 neurons . "It's good to start with a logical prediction and then let your brain surprise you," says Parker.

Antipsychotics do not work in 30% of people
The notion that D1 receptors may be a more important target upends decades of research in a $15 billion market for famously erratic drugs. Antipsychotics do not work in 30% of people who try them. They are riddled with side effects, from extreme lethargy to unwanted facial movements, and rarely address the cognitive symptoms of psychosis, such as social withdrawal and poor working memory.

The assumptions about D2s were profound, recalls 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 textbook knowledge," she confirms.

"I was surprised, but in a way excited" by the conclusions of the new study, he continues. Now "we can begin to understand the real mechanism . And that is the first step to reaching much better treatments," she says.