Antipsychotic medications are widely used for schizophrenia, bipolar disorder, and other psychiatric conditions, but long-term use can cause side effects such as cognitive decline. Now, a study done in mice suggests that some antipsychotic drugs may impair memory partly by disrupting gut microbes that produce the protective compound ergothioneine, and restoring that pathway could help reduce these side effects.

The findings, published in Cell Host & Microbe, suggest that targeting the gut microbiota-ergothioneine pathway may offer a new way to prevent or treat cognitive side effects of antipsychotic drugs.

Previous studies suggested that antipsychotics may damage the brain, but the reasons were unclear. Because gut microbes can make chemicals that influence brain function, researchers led by Mingxuan Zheng at Xuzhou Medical University in Xuzhou, China, hypothesized that antipsychotics may disrupt beneficial microbial products and contribute to memory and learning problems.

To test this idea, the researchers measured gut bacteria, blood and brain metabolites, and memory in mice given the antipsychotics olanzapine, risperidone, or clozapine.

Cognitive decline

In mice, olanzapine treatment changed gut bacterial communities, with beneficial Cyanobacteria declining and other microbes increasing. The gut’s protective mucus layer became thinner and bacterial toxins leaked more easily into the bloodstream. Olanzapine-treated mice also had damaged neurons in the hippocampus, a brain region important for memory, and they performed worse on memory tasks than untreated mice.

To test whether the altered microbiota was responsible for cognitive decline, the researchers transferred stool microbes from olanzapine-treated mice into healthy mice. Recipient mice showed weaker gut barrier and poorer performance on memory tests. Instead, giving healthy microbes to olanzapine-treated mice improved gut health and cognition. 

Further analyses showed that ergothioneine, which is made by certain microbes and helps protect cells from oxidative stress and inflammation, was strongly reduced in mice after olanzapine treatment. Blood levels of ergothioneine were also lower in people taking olanzapine.

Improving cognition 

Supplementing mice with ergothioneine restored neuron structure and improved scores in memory tests. Giving mice two ergothioneine-producing Cyanobacteria strains also improved cognition, the researchers found.

Olanzapine appears to increase oxidative stress in the brain, while ergothioneine reduces this stress by lowering the levels of a stress-related protein called PTP1B. Restoring PTP1B in neurons largely prevented cognitive problems, the authors found.

“Our findings identify depletion of microbiota-derived ergothioneine as a mechanism underlying antipsychotic-induced cognitive impairment, highlighting therapeutic strategies to mitigate this side effect,” they say.