Schizophrenia Drug May Have Been Off Target For Decades, Study Finds

Schizophrenia Drug May Have Been Off Target For Decades, Study Finds

A study that looked at the brains of live rats showed for almost 70 years we already targeting the wrong neurons in our design antipsychotic medication.

Deciphering the vast web of brain cells and determining how drugs act on them is a difficult task. Using miniature microscopes and fluorescent labels, a team of researchers led by Northwestern University neuroscientist Seongsik Yun discovered that effective antipsychotic drugs attach to a different type of brain cell than scientists had thought.

Just as studies suggest that depression may not be a chemical imbalance in serotonin levels, our understanding of schizophrenia treatment may need to be rethought if widely used antipsychotics target different neurons than expected.

“There is an urgent need to understand the neural circuits that drive psychosis and how they are affected by antipsychotic drugs,” Yun and colleagues wrote in the published paper.

As neurologist and senior author of the study Jones Parker puts it Cable Max G. Levy, most antipsychotic drugs – including the first to be approved in 1954, chlorpromazine – were discovered by chance. “So we don’t know what they actually do to the brain.”

After discovering it, scientists paid attention to the depressing drug common symptoms of schizophrenia such as mania, hallucinations, and delusions, appear to affect the brain’s dopamine system.

These antipsychotic drugs, they studied, suppressed the transmission of dopamine between brain cells, and were the most potent compatible with a specific type of dopamine receptor labeled D2.

Brain cells are called spiny projection neurons, which pack in and out of striatum brain, express D1 or D2 receptors. Unlike D1 receptors, which excite the brain’s dopamine system, The D2 receptors calm him down.

Linking the potency of antipsychotic drugs to D2 receptors gave rise to the idea that in schizophrenia, the striatum is flooded with dopamine, a chemical imbalance that is helped by antipsychotics.

But new drugs designed specifically to target D2 receptors are doing little to relieve psychosis. And no one has actually tested in animal models of psychosis whether decades-old antipsychotic drugs preferentially bind to D2 receptors, so their precise mechanism of action remains unclear.

To investigate, Yun, Parker and their team injected mice with one of four drugs used to treat psychotic illnesses, and watched how the animals behaved and how their brain cells responded.

They found that haloperidol and olanzapine, two older but efficacious antipsychotics, had some effect on D2 spike neurons, but their interaction mostly occurred on D1 neurons.

Clozapine, a newer, stronger antipsychotic with fewer side effects, avoids D2 neurons, and oversuppresses D1 cells, which may somehow “explain its clinical advantage, especially for treatment-resistant schizophrenia,” the researchers said.

Meanwhile, MP-10, a failed drug candidate in schizophrenia clinical trials, remained glued to D2 neurons. In fact, the MP-10 made D1’s abnormal activity even worse.

In other words, the clinical efficacy of a drug is closely related to its interaction with D1 neurons; those that normalize overactive D1 neurons best alleviate psychosis — a finding that overturns our understanding of these drugs.

“These findings provide a new explanation for the efficacy of antipsychotic drugs,” the researchers wrote. They suggest D1 spiny neurons, not D2-expressing cells, “may be a major driver of psychosis” and that normalizing their activity may be “a key indicator of antipsychotic effectiveness.”

While this finding is a blow to decades of research, it helps explain why some antipsychotic drugs like clozapine work while others don’t. Although we must remember that dopamine is not the only neurotransmitter associated with psychosis.

The findings also offer a glimmer of hope that researchers can correct course and use this new insight to design much better schizophrenia treatments. Treatment that can not come immediately.

The study has been published in Natural Neuroscience.

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