Can ketamine treat depression? The answer may lie in a mysterious brain cell

To treat depression, the neurons which control the hormones serotonin and dopamine in our brains seem to get all the attention. The evidence so far suggests people who have major depressive disorder may benefit from an artificial boost to these chemical messengers — so psychiatrists prescribe drugs like Prozac, claiming to do just that.

But here's the rub: The drugs don't always work. According to the National Institute of Mental Health, some 7 percent of all adults in the United States will experience at least one depressive episode in their lifetime, with the most affected group aged 18 to 25 years.

In the quest to find treatments, scientists are starting to take a closer look at another, less familiar contributor to the brain's ability to function. A new study suggests these distinctive, star-shaped brain cells may play a far more significant role in depression than scientists had believed — they could also help explain why ketamine is of such great interest as a treatment.

These cells are astrocytes, and if you have never heard of them, that is ok.

“Without the astrocytes, the connections within brain areas would be impossible to control and regulate.”

Here's the background — Astrocytes are a kind of cell known as “glia,” which dwell among neurons in the brain. Neurons send information through the brain and body using synapses, and astrocytes connect these synapses. In fact, an astrocyte might connect as many as two million synapses at any one time. They also regulate much of their activity, make sure these brain cells get enough nutrients to transmit signals, and they help blood flow in the brain.

In other words, astrocytes are essentially the brain's executive valet.

Javier Miguel-Hidalgo is a professor at the University of Mississippi Medical Center. He has studied astrocytes and their role in mood disorders for most of his decades-long career, and he was not involved in this most recent study. He tells Inverse the role of these starry cells may be little known, but it cannot be overstated.

“Without the astrocytes, the connections within brain areas would be impossible to control and regulate,” Miguel-Hidalgo says.

“For example, what happens if there is no water at an American football match? There's no water. And nobody maintains the grass... What happens? Football disappears, most likely,” he says.

What's new — Building on a growing body of work pointing to the role of these cells in mood disorders like major depression, study lead author Liam O’Leary, a Ph.D. candidate at McGill University, and his team have effectively solidified the link between astrocytes and major depression.

By looking directly at three critical regions of the brains of people who died by suicide during major depressive episodes and comparing them to typical brains, the team found no significant change in the shape of the astrocytes between the brains. But what they did find was intriguing: In the brains of people who had died during a major depressive episode, all three areas had far fewer of these maintenance cells than expected.

The difference in astrocyte amounts isn’t new, but O'Leary tells Inverse the extent of the differences was surprising.

The researchers saw as much as a two to five times difference in the number of astrocytes between both groups. Not only that, but they found this to be especially true for two kinds of astrocyte.

“Together, [these results] strengthen the idea that astrocytes are not only affected in depression but affected in a way that we kind of need to acknowledge at the level of treatment and approaches and ways of thinking about depression,” O’Leary says.

“I'm actually surprised that no one has thought of making a drug that targets astrocytes.”

How they did it — The study, which was published in the journal Frontiers in Psychiatry, involved looking at slivers of donated brain tissue taken from ten human donors who had died by suicide during a major depressive disorder, as well as tissue samples taken from donors who did not.

One of the regions the researchers were most curious about was the prefrontal cortex. This region plays a role in executive functioning — motivation, sequencing actions, and evaluating others' and our own actions and perceptions. The researchers found large reductions in the number of expected astrocytes in this area.

The result may go some way to explaining why these same executive functioning skills are generally reduced in major depressive disorder. People with depression can have trouble planning ahead, or acting with a goal in mind, for example.

Why it matters — These results go beyond offering some explanation for depression's pernicious manifestation. They also offer a road forward for new treatments.

Major depression can be complex and difficult to treat quickly, a delay which can prove fatal. Pinpointing how depression makes itself manifest in the physiology of the brain, and finding biological signatures of the disorder, like astrocytes, can be critical for understanding and better treating the condition.

Astrocytes may actually be key players in the mechanism for a drug known mostly for its popularity with club kids at raves: ketamine. In 2019, the FDA approved a ketamine-like nasal spray for “treatment-resistant depression” in adults, and some animal studies point to its interaction with astrocytes.

What's next — Right now, antidepressants aren’t made with these particular cells in mind. But there is some evidence to suggest astrocytes are affected by traditional antidepressants. Yet astrocytes are quite different from the neurons these antidepressants target — they can regenerate, for example.

“I think astrocytes would be a good drug target because they are quite adaptable as cells,” O’Leary says.

There’s still much to learn about these star-shaped cells and depression since the study was constrained by its small size and limited to white, male brains. Researchers still want to learn more about the relationship between depressive episodes and astrocytes, and whether or not the effect would be the same across genders, ages, and races.

O'Leary is confident the evidence suggests astrocytes are “a core mechanism” in depression.

“I'm actually surprised that no one has thought of making a drug that targets astrocytes when we have these massive changes. And I think we probably should.”

If you or someone you know is affected by depression, please find help now. The International Association for Suicide Prevention provide a list of crisis centers across the world that can offer support in your region.

National Suicide Prevention Lifeline: 1-800-273-8255

Abstract: Post-mortem investigations have implicated cerebral astrocytes immunoreactive (-IR) for glial fibrillary acidic protein (GFAP) in the etiopathology of depression and suicide. However, it remains unclear whether astrocytic subpopulations IR for other astrocytic markers are similarly affected. Astrocytes IR to vimentin (VIM) display different regional densities than GFAP-IR astrocytes in the healthy brain, and so may be differently altered in depression and suicide. To investigate this, we compared the densities of GFAP-IR astrocytes and VIM-IR astrocytes in post-mortem brain samples from depressed suicides and matched non-psychiatric controls in three brain regions (dorsomedial prefrontal cortex, dorsal caudate nucleus and mediodorsal thalamus). A quantitative comparison of the fine morphology of VIM-IR astrocytes was also performed in the same regions and subjects. Finally, given the close association between astrocytes and blood vessels, we also assessed densities of CD31-IR blood vessels. Like for GFAP-IR astrocytes, VIM-IR astrocyte densities were found to be globally reduced in depressed suicides relative to controls. By contrast, CD31-IR blood vessel density and VIM-IR astrocyte morphometric features in these regions were similar between groups, except in prefrontal white matter, in which vascularization was increased and astrocytes displayed fewer primary processes. By revealing a widespread reduction of cerebral VIM-IR astrocytes in cases vs. controls, these findings further implicate astrocytic dysfunctions in depression and suicide.