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Antipsychotic Drugs May Work Differently to How We First Thought

Neurons sending out electrical signals.
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Years of drug development have produced medicines that help the millions of Americans who have schizophrenia find relief from their symptoms. But these drugs are far from perfect. Side effects and uncertain efficacy mean that the status quo isn’t good enough – we need new drugs for this condition.

In a stride toward this goal, scientists from Northwestern Medicine have paved a new path toward more effective drugs for schizophrenia and provided results that suggest the way these drugs work is more complex than first thought. These researchers have surpassed traditional methods, which primarily rely on evaluating the effects of antipsychotic drug candidates on mouse behavior. The new study’s innovative approach could show greater promise in predicting the efficacy of these drugs in patients.

The study was published in Nature Neuroscience.

“A landmark finding”

That promise comes from a key finding about antipsychotic drugs. These compounds inhibit production of the neurotransmitter dopamine, which is thought to contribute to schizophrenia symptoms. The new study suggests that antipsychotics cut dopamine output by interacting with a different type of brain cell than previously thought.

“This is a landmark finding that completely revises our understanding of the neural basis for psychosis and charts a new path for developing new treatments for it,” said lead investigator Jones Parker, assistant professor of neuroscience at Northwestern University Feinberg School of Medicine.” It opens new options to develop drugs that have fewer adverse side effects than the current ones.”

What is schizophrenia?

Schizophrenia is a brain disorder that affects roughly 1% of the population. The condition has a complex array of symptoms, divided into three classes: positive, negative and cognitive. Positive symptoms include hallucinations and delusions, negative symptoms include loss of interest in daily activities and difficulty displaying emotions and cognitive symptoms include troubles with attention and memory. Antipsychotic drugs neutralize the effects of many positive symptoms but are less effective at dealing with other symptom classes. Even worse, 30% of patients do not respond to antipsychotics, and these drugs have side effects that can affect how patients move and control their bodies.

The molecular basis of schizophrenia

Dopamine is produced by cells in a brain region called the striatum. There are two neuronal cell types present in the striatum: those bearing D1 dopamine receptors and those bearing D2 receptors. The receptors are like coin slots on an arcade machine that runs on neurotransmitters. When a molecule of dopamine arrives in the slot, it activates the neuron and consequent signaling cascades. Imagine two machines with differently sized slots – these are the D1 and D2-bearing neurons. Antipsychotic drug molecules are the right size to block D2 receptor slots, but not D1. It was therefore thought that these drugs’ action on D2 receptors was the key element in their success in treating the symptoms of schizophrenia.  

The researchers made this discovery by leveraging an imaging-based assay that used tiny microscopes to see how different drugs affected dopamine-expressing neurons in the mouse brain in real time.

Parker said that the findings refuted the key theory about how antipsychotics work and suggested subsequent work would need to reconsider the mechanisms by which antipsychotics act to fully consider the role of D1 receptor modulation. “Our study exposed our lack of understanding for how these drugs work and uncovered new therapeutic strategies for developing more effective antipsychotics,” Parker said.

Reference: Yun S, Yang B, Anair JD, et al. Antipsychotic drug efficacy correlates with the modulation of D1 rather than D2 receptor-expressing striatal projection neurons. Nat Neurosci. 2023:1-12. doi:10.1038/s41593-023-01390-9

This article is a rework of a press release issued by Northwestern University. Material has been edited for length and content.