Six forms of depression identified – Mental illness manifests itself in different biotypes

Neuronal differences: Depression is not the same as depression – there are apparently at least six different subtypes, as researchers have discovered. These biotypes can be identified using brain scans. Because they are based on different functional disorders, not all of them respond to common antidepressants. In the future, brain scans could make diagnosis easier and identify the most promising treatments.

Mental illnesses are often difficult to diagnose and even more difficult to treat. For around 30 percent of people suffering from depression, none of the known treatments work. Neither antidepressants nor psychotherapy provide relief. For two-thirds of those affected, the available treatments reduce the symptoms of depression, but do not make them completely healthy again.

Therapies often ineffective

One reason for this is that there is no good evidence to predict which type of treatment will help with depression. Doctors and sufferers often try different medications one after the other until one works. However, this can take months or years, or it can have no effect at all. During this waiting period, depression often gets worse.

“It’s very frustrating not to have a better alternative to this one-size-fits-all approach to depression,” says senior author Leanne Williams of Stanford University, whose partner also suffers from depression. Since then, she and her team have been looking for a way to treat patients in a more targeted and individualized way. “The goal of our work is to find out how we can get it right the first time,” says Williams.

A look into the brains of mentally ill people

To do this, the researchers led by Williams and lead author Leonardo Tozzi from Stanford University have now examined the biological processes involved in mental illnesses in more detail. Using functional magnetic resonance imaging (fMRI), they observed the brain activity of 801 people who suffered from depression or anxiety disorders, as well as 137 healthy people. They focused on those brain regions that previous studies have shown to be associated with these illnesses.

During the scans, the subjects either rested or completed various tasks that challenged them mentally and emotionally. 250 of the study participants also received treatment in the form of a common antidepressant or talk therapy for a second test run. Tozzi and his colleagues then evaluated the fMRI images using artificial intelligence, which sorted the images into groups.

Six different patterns of brain activity

The surprising result: The brain scans revealed six different activity patterns in the patients in the regions examined. For example, one of these biotypes (DC+SC+AC+) showed a fundamentally higher activity in three neural circuits that are involved in the processing of attention and rest. These areas are also used for problem solving. In another biotype (AC-), however, one of these circuits responsible for attention was significantly less active than in healthy people.

Another biotype (NSA+PA+) showed conspicuous activity patterns when solving emotional tasks. The affect circuits in the brains of these people were overactive, which caused negative and positive affects to sad and happy stimuli, respectively. However, the most common biotype (CA+) was one in which the neurons for cognitive control were overactive.

Also interesting: One of the two rarer of the six identified biotypes is neurologically unremarkable. The brain activity of these test subjects with mental illness did not differ from that of healthy people. However, Tozzi and his colleagues suspect that they would find biological abnormalities here too if they looked at the entire brain rather than just selected regions. The observation suggests that not all neuronal connections are yet known in depression, according to the team.

Types of depression correlate with symptoms and treatment success

Tozzi and his colleagues conclude that depression can be differentiated into at least six biotypes. This also fits with the fact that the different biotypes are associated with varying degrees of severity and sometimes different symptoms. Those affected in the NSA+PA+ and CA+ groups, for example, felt even less joy than the other test subjects. The CA+ subtype was also more anxious, while the NSA+PA+ type brooded more. People with the AC- biotype, on the other hand, suffered from less tension.

The therapeutic success also differed depending on the biotype, as the psychiatrists found. Accordingly, the drug venlafaxine alleviated the depression symptoms in the test subjects with the CA+ subtype significantly better than in the other patients.

Why talk therapy doesn’t help everyone

For the biotype with the three overactive brain regions used for problem solving (DC+SC+AC+), behavioral and talk therapy helped the most, the researchers report. For the biotype in which the nerves controlling attention were less active (AC-), however, this type of treatment helped the least.

For co-author Jun Ma from the University of Illinois Chicago, these observations make sense. Because those affected can more easily learn the problem-solving practices taught in talk therapy and implement them in everyday life if the areas of the brain required for this are more active, she reports. People with a low level of attention, on the other hand, benefit less from this form of therapy.

Find effective treatment faster

“This is the first time that we have been able to show that depression can be explained by various brain dysfunctions,” says Williams. Depending on the type of depression and biotype, the brain scans now result in different treatment approaches. The study thus opens up personalized medicine for mental health for the first time, according to the team. In the future, brain scans could therefore help to develop helpful and overall more effective therapies more quickly. In a similar study, Williams and her team were already able to double their accuracy in choosing treatment using MRI scans.

In follow-up studies, the psychiatrists now want to repeat their experiments with a larger test group and other treatment methods. New types of medication other than standard antidepressants will also be researched. This should ensure an even more precise allocation and the best possible therapy.

In an experimental procedure, the researchers are already using the brain scans to diagnose and treat patients at Stanford University. In doing so, they are developing new standard protocols that other practicing psychiatrists can later use. (Nature Medicine, 2024; doi: 10.1038/s41591-024-03057-9)

Source: Stanford University School of Medicine

18 June 2024 – Claudia Krapp