A new study debunks the theory that depression is associated with brain asymmetry.

A new study with thousands of participants has found no differences between people with a depression diagnosis and people classed as “healthy control subjects.” The study examined asymmetrical brain volume.

Asymmetrical brain activation is common in humans and varies between individuals. For instance, right- or left-handedness and left-hemisphere use for language are common asymmetrical brain usage in humans. Previously, researchers have theorized that brain asymmetry may be associated with the experience of depression. Small studies have found slight effects suggesting that people with depression have more brain asymmetry in certain areas.

In the current study, the researchers intended to clarify these inconclusive findings by conducting a study large and powerful enough to detect even minuscule differences in their analysis of MRI (brain scan) results. Their analysis, however, found no differences.

“No signiﬁcant differences of brain structural asymmetry were found between individuals with major depression and unaffected control subjects, for any cerebral cortical or subcortical asymmetry measure, in an unprecedented sample size of over 5,000 subjects.”

The research was led by Clyde Francks at the Max Planck Institute, the Netherlands, and involved the ENIGMA Consortium, a group of international researchers using large samples to examine brain differences for mental health concerns.

In one test, the researchers analyzed the data from 2,256 people with a diagnosis of depression and compared that data to 3,504 people considered a “healthy control group” They looked at the thickness and surface area of 34 different cortical regions of the brain.

In another test, the researchers compared the volume of eight parts of the brain (subcortical regions) in 2,540 people with the diagnosis, and 4,230 “healthy controls.”

In total, the authors examined 42 different areas of the brain. In each one, the people with the diagnosis were no different from the people who did not have depression.

Having found that there was no difference in brain asymmetry between the two groups, the researchers then attempted a number of other tests. They wanted to see if subcategories might be responsible for some brain differences instead. However, their results suggest that none of the subgroups had differences in brain asymmetry either:

“Asymmetry measures were not signiﬁcantly associated with medication use, acute compared with remitted status, ﬁrst episode compared with recurrent status, or age at onset.”

There were no brain differences in people taking medication, people classified as having recovered from depression, people who had depression for the first time, people who had multiple episodes of depression, or age at which the first episode of depression occurred when compared to “healthy controls.”

The researchers also checked to see if a particular gender or age exhibited brain differences, and again came up negative. The researchers also note that previous findings may have been false positives due to small sample sizes, especially in light of poor reproducibility. They also cite a recent large meta-analysis that found no symmetry differences.

Although asymmetry appears to be a dead-end, previous findings of brain differences in depression by the ENIGMA group suggested that depression was associated with a lower hippocampal volume on average. However, the slight average difference means that very few people actually have a smaller hippocampus—almost everyone with the diagnosis of depression has the same brain volume as someone without the diagnosis. Thus, these findings may be clinically irrelevant, as suggested by researchers like Eiko Fried of the University of Leuven, Belgium (not affiliated with this study).

According to Fried, in reference to the previous study,

“We conclude that the study by Schmaal et al. provides the so far strongest piece of evidence that, at least regarding the subcortical regions studied here, brains of depressed patients are remarkably similar to brains of healthy individuals, suggesting that numerous prior conflicting results in much smaller samples were false positives.”

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de Kovel, C. G. F., Aftanas, L., Aleman, A., Alexander-Bloch, A. F., Baune, B. T., Brack, I., . . . Francks, C. (2019). No alterations of brain structural asymmetry in major depressive disorder: An ENIGMA consortium analysis. American Journal of Psychiatry, (Link)