Major depressive disorder (MDD) contributes significantly to the global burden of disease and is a leading cause of disability worldwide. Understanding the pathophysiology of the disease and new therapies are urgently needed as treatment resistance is common and occurs in up to 30% of MDD patients.

Previous studies showed altered inflammatory marker levels in depressed patients. In addition, chronic inflammatory conditions such as rheumatism, inflammatory bowel disease and multiple sclerosis have all been linked to depression. These findings imply that brain inflammation may contribute to depression. But is it so?

A new study by Karel Scheepstra and his team analyzed post-mortem human brain tissue from people with depression. This brain tissue was donated to the Dutch Brain Bank for Psychiatry (NHB-Psy) by recently deceased people who donated their brains. So what did they discover? In people with depression, the brain’s microglial cells, a specific type of immune cell, are less active. Contrary to expectations, immune cells are suppressed, which is the reverse of inflammation.

Microglial cells maintain synapses, allowing neurons to communicate efficiently. They also constantly scan the central nervous system for damaged neurons, synapses and pathogens.

Only the microglial cells close to the neurons in the samples from depressed individuals showed reduced activity. So the group investigated whether microglial cells receive signals from neurons that make them less active when someone is depressed. And this did come true.

Scientists used fresh tissue immediately after death to isolate microglia during the study. They then compared the tissues between depressed people and controls.

Karel Scheepstra (researcher involved in the research and working as a psychiatrist at Amsterdam UMC): “We saw abnormal microglia in depressed patients, with the greatest abnormalities in patients who were most depressed just before death. Interestingly enough, abnormalities were only seen in the gray matter and not the white matter of the brain. This suggests a likely interaction between the microglia and the structures in the gray matter: the neurons and synapses.”

“We also looked at the type of adjustments. We’ve hypothesized for years that depression is related to brain inflammation, but we’re now seeing the exact opposite: not neuroinflammation, but rather an immune-suppressed type of microglia.”

“We called them ‘depressed microglia’ and wondered how this is possible. The proteins CD200 and CD47 are located in brain cells and synapses. They interact with microglia and act as a kind of “don’t eat me” signal, so to speak. We saw that these proteins were elevated, resulting in suppressed microglia, possibly preventing them from cleaning up damaged connections.”

“Depression is thought to have something to do with a change in neuroplasticity: the ability to make new connections between neurons. A relatively new antidepressant is ketamine, which intervenes in this process and causes more compounds to grow again. In this study, we show that there is a disrupted neuron-microglia interaction. The next step would be to see what exactly the consequences of the inactive microglia are for the maintenance and formation of connections between neurons.”

“Knowing where things go wrong in the process can provide starting points for new medication. Can we make these microglia more active again? And what effect does this have on the course of the disease? For now, we have shown that the brains of people who were depressed during their lifetime show altered cell activity. This gives us a better insight into what goes wrong, which we can then build on.”

Magazine reference:

  1. Karel WF Scheepstra, Mark R. Mizee et al. Microglia transcription profiling in major depressive disorder shows inhibition of microglia in the cortical gray matter. Biological psychiatry. DOI: 10.1016/j.biopsych.2023.04.020