Why do some people struggle to recover from depression?

Depression is more than just feeling sad. Many people with depression experience sleep problems and difficulties with concentration, planning or remembering, sometimes even after treatment. These symptoms make it harder to resume everyday life. In addition, depression treatments are often less effective for these individuals, or their depression returns more quickly. Yet we still do not fully understand why sleep problems and cognitive difficulties are so closely linked, or why some people with depression experience these problems much more severely than others.

Initiated by clinical neuropsychologist Esmée Verwijk (Amsterdam UMC), psychiatrists Didi Rhebergen (GGZ centraal)  and Jeanine Kamphuis (UMCG) are working together with researchers from the Netherlands Institute for Neuroscience on a groundbreaking new research idea. A project group of ten additional clinicians and neuroscientists from across the Netherlands is contributing to the project. Their shared goal is to better understand what happens in the brain of people with depression who experience sleep and cognitive problems. This could be an important step towards entirely new treatment approaches.

“We know that cognitive complaints and sleep problems are associated with poorer recovery, but we still do not understand why one patient is severely affected while another experiences hardly any of these problems,” says Esmée Verwijk. “That is exactly the question we hope to answer with this research.”

Sleeping while awake

The researchers believe that poor sleep causes small parts of the brain to briefly enter a kind of “sleep mode” during the day, even though the person remains awake. This phenomenon, known as local sleep, can lead to lapses in concentration, mistakes and mental slowing. It may be a key link between sleep problems and the cognitive complaints experienced by many people with depression.

Poor sleep also disrupts the maintenance of myelin in the cerebral cortex. Myelin is a protective layer surrounding nerve fibres that enables brain cells to communicate rapidly with one another. When this layer becomes thinner, communication between brain cells slows down. The researchers expect that this increases the likelihood of local sleep during the day, as well as the risk of cognitive problems.

This disruptive process may progress more rapidly and more severely in some people with depression. Genetic risk for depression appears to be concentrated in genes that are important for oligodendrocytes, the brain cells responsible for maintaining myelin. These cells may therefore already be more vulnerable in people with depression. Indeed, previous studies have shown that certain regions of the cerebral cortex contain less myelin in people with depression.

From the sleep laboratory to brain imaging

The team will investigate these possible mechanisms in 75 people with depression. Participants will first wear a sleep monitor at home for several days before spending a night in the sleep laboratory. There, researchers will measure their brain activity both during sleep and while they perform memory and attention tasks during the day. In addition, co-applicant Wietske van der Zwaag will use a newly developed, highly detailed MRI technique to measure the amount of myelin in different regions of the brain.

Bringing the puzzle pieces together

What makes this research unique is that it brings together different scientific disciplines. Clinical knowledge about depression is directly linked to fundamental research on sleep, cognition and brain function.

“Much of this knowledge already existed, but in separate fields,” says sleep researcher Eus van Someren. “By bringing these puzzle pieces together, we can finally test whether our ideas really hold true in patients.”

Co-applicant Mohit Dubey, who studies myelin and brain cells in the research group of Maarten Kole, also sees this as the strength of the project. “This truly is a bench-to-bedside project—and back again,” he says. “We combine insights from fundamental research with what we observe in the clinic. It is precisely this interaction that allows us to understand where these symptoms come from and, ultimately, how we can treat them.”

Towards better treatments

By combining all these data, the researchers hope to discover how sleep, brain activity and myelin together contribute to recovery from depression. In the longer term, this could lead to new, more personalised treatments, such as therapies specifically targeting sleep or new forms of brain stimulation.

The researchers also hope to identify an objective measure of the brain changes associated with these symptoms. “For disorders such as epilepsy, we have clear biological markers,” says Dubey. “For depression, we still lack such an objective measure. If we can identify one, we will be able to tailor treatments much more precisely to individual patients.”

The project is a collaboration between clinicians Esmée Verwijk, Didi Rhebergen and Jeanine Kamphuis, and Netherlands Institute for Neuroscience researchers Mohit Dubey, Maarten Kole, Wietske van der Zwaag and Eus van Someren. It is one of two research projects selected within a new collaborative programme between the Netherlands Institute for Neuroscience (NIN) and Psychiatry in the Netherlands. The programme promotes close collaboration between clinicians and fundamental neuroscientists, with the aim of improving our understanding of the biological basis of psychiatric disorders so that fundamental discoveries can more rapidly be translated into clinical practice.