When the book Men are from Mars Women are From Venus hit the shelves in the 1990s, the ground almost shook. The book sold in the millions, confirming every sitcom writer’s fantasy and triggering many endless debates. But there was more to the book’s impact than just this.

Fast forward to 2017 and consider the National Public Radio review of the book Testosterone Rex: Myths of Sex, Science, and Society. The review quoted the book’s author Cordelia Fine, who said: “Testosterone Rex misrepresents our past, present, and future; it misdirects scientific research; and it reinforces an unequal status quo.”

By “Testosterone Rex,” she refers to the over-generalized notion that women and men were essentially different. But things are not always clearly separated.

In fact, the more we look at this matter, the more we find that things are complex and there are few things that are clear. To emphasize this even more, a study from the University of Colorado Boulder addressed gender differences in the way we experience drugs for mental illness. The study findings were published in the journal eLife, and they shed new light but also raise more questions about how the minds of men and women are different.

AKT behavior

Over the years, molecular studies have led to the development of many pharmacological treatments for psychiatric illnesses. However, with all these advancements, the effectiveness of available therapies still remains limited.

The researchers said the situation may, at least in part, be due to not having enough information “about the specificity of neuromolecular signaling pathways involved in the manifestation of individual behaviors and processes associated with the symptomology of psychiatric disorders as well the specific signaling effects within different neural cell types and those impacted by sex.”

Here’s the thing: most behavioral mouse studies are carried out using only males. When a finding is successful on mice, it can then be trialed on humans eventually, but it still started from just male mice — and this is a problem. If we tailor treatments based on this, we may end up with treatments biased against women — and this is just one of the possible biases that can creep up in this sort of study. Charles Hoeffer, an assistant professor of integrative physiology at the Institute for Behavioral Genetics, and one of the study authors, explains:

“The ultimate goal is to find the kink in the armor of mental illness—the proteins in the brain that we can specifically target without impacting other organs and causing side effects.” Hoeffer maintained that personalization was key. “We need to stop hitting every mental illness with the same hammer.”

Researchers wanted to further explore gender differences in their study. The team found that “a key protein in the brain called AKT may function differently in males than females. The study also offers a closer look at where, precisely, in the brain things may go wrong, marking an important step toward more targeted and less harmful therapies.”

It wouldn’t be the first time sex-dependent differences are called out in mental health research — the matter has been amply documented before. Citing other studies, for example, this recent study notes that “Women are disproportionately impacted by affective disorders” while, in men, schizophrenia was more prevalent and yet, over the course of aging, schizophrenia impacted women at higher rates. Researchers also found that women were more responsive to available treatments for schizophrenia and in female mice, ketamine exerted more potent and rapid effects.

The study explored that “key protein in the brain called AKT,” as mentioned earlier. Quoted in CU Boulder Toay, Hoffer discussed AKT: “Let’s say you see a shark and you’re scared and your brain wants to form a memory. You have to make new proteins to encode that memory.” AKT cranks the gears up on downstream proteins in the memory factory. We can’t learn new memories without it nor extinguish old ones to make room for new, less harmful ones. The team noticed how different gendered mice responded to the loss of various AKT isoforms.

Interestingly, National Institutes of Health guidelines in the past six years began to require researchers to include both male and female animals in studies. The New York Times back in 2014: “Name a new drug or treatment, and odds are researchers know far more about its effect on men than on women. From sleeping pills to statins, women have been blindsided by side effects and dosage miscalculations that were not discovered until after the product hit the market.”

Memories in balance

The study team found that the difference between males and females was nothing to sneeze at. They found the difference between males and females to be “so great it became the focus of our work,” Hoeffer said. “It was like night and day.”

CU Boulder Today said “male mice whose AKT1 was functioning normally were much better than those missing the protein when it came to “extinction learning” – replacing an old memory, or association, that’s not useful anymore. (Imagine letting go of the memory of your favorite route home from work because you’ve moved, or disassociating a loud sound with danger).” For female mice, it didn’t make much of a difference.

AKTs include AKT2, found in star-shaped brain cells and often implicated in brain cancer. AKT3 appears to be important for brain growth and development. AKT1, in combination with AKT2 appears to be critical for learning and memory. What’s next? Beyond AKT, there may be other proteins in the brain contributing to the differences, said Hoeffer, “with different flavors serving different purposes or acting differently in men and women.”