The science behind lifestyle's role in preventing depression

Given the rising rates of depression, a recent paper in Nature Mental Health looks at the effect of a range of lifestyle factors in relation to the brain structure, immune function, metabolic pathways, and genetic mechanisms, that are responsible for depression.

The brain structure, immunometabolic and genetic mechanisms underlying the association between lifestyle and depression
Study: The brain structure, immunometabolic and genetic mechanisms underlying the association between lifestyle and depression. Image Credit: MMD Creative/


Depression (properly called “major depressive disorder” MDD) is a debilitating disorder that reduces a person’s ability to function and severely impairs quality of life. While it can be prevented or mitigated to some extent by lifestyle modifications, not much is known about how these factors protect against depression.

Prior research suggests that lifestyle and depression share similar neurobiological pathways that could help modify the risk of mental illness through lifestyle adjustments.

Myokines, chemicals from muscle cells, are released during exercise. They boost the mood via hippocampus regulation. Meanwhile, excess food consumption coupled with too little physical activity suppresses stress responses at a cellular level, and poor sleep patterns disrupt the body rhythms.

Social isolation, smoking, and excessive drinking also disrupt metabolic and brain health. All of these have been shown to contribute to a higher depression risk.

Unlike earlier studies, which have been largely focused on one lifestyle factor, the current study included a wide range of factors. In addition, considering the complex genetic risk of mental illness, the researchers used the polygenic risk score (PRS) to modify lifestyle-associated risk.

Moreover, they looked at the brain, where genetic risk might be expressed first, to identify the underlying mechanisms of depression and the variations in immune function in those at genetic risk. They postulated the existence of shared pathways for genetic and lifestyle contributions to depression.

The UK Biobank provided abundant prospective data in all these areas and was tapped for the purposes of the study.  

What did the study show?

The researchers looked at almost 290,000 participants, the mean age being 57.5 years. They aimed to explore seven lifestyle factors thought to reduce the risk of ill-health and depression.

The factors they looked at were moderate drinking, a good diet, exercise, proper sleep, no smoking, no more than a moderate degree of sedentary behavior, and social mixing.

People were categorized as having favorable, unfavorable, or intermediate lifestyles, depending on how many of these factors they had. While just over 1% had unfavorable lifestyles, 39% and 60% followed intermediate and favorable lifestyles, respectively.

Over the nine years of follow-up, approximately 13% developed depression.

The study found that all seven lifestyle factors reduced the risk of depression. They also found a steady decrease in the risk of depression from unfavorable to favorable lifestyle, from a risk reduction of 17% when only one factor was present to 72% lower risk with all seven. Each one-point increase in the healthy lifestyle score was correlated with a risk reduction of 15% in quantitative terms.

Among them, healthy sleep, never smoking, and social mixing all decreased the risk of depression by approximately a fifth each. Physical activity and a less sedentary lifestyle reduced the risk by about 13-14% each.  Social interactions were best correlated with a reduced risk of recurrent depression.

The risk for the intermediate lifestyle was 40% lower than that of the unfavorable lifestyle. There was a 57% reduction in the favorable lifestyle.

When the genetic risk was also accounted for, using the PRS, in almost 200,000 people, the risk of depression was 64% lower when both genetic and lifestyle risk was low compared to those who had a high genetic risk and followed an unfavorable lifestyle.

lifestyle may not be substantially altered by the genetic risk for depression and lifestyle has a strong protective role across different levels of polygenetic risk population.

Zhao et al. (2023)

Mendelian randomization, which is less likely to be impacted by reverse causation or confounding than observational studies, supports the protective effect of lifestyle on depression risk.  The risk for depression was reduced by 45% with a healthy lifestyle. Each one-point increment in lifestyle was associated with a 35% decline in depression risk.  

There is a potential bidirectionality in this association, which was further confirmed by the other parts of the study.

The second part of the study was performed by correlating the lifestyle factors with brain imaging, in a subset of almost 33,000 people with the available data. This showed that several regions of the brain were related to lifestyle habits, such as the pallidum, thalamus, and superior frontal cortex. A healthier lifestyle was associated with large brain volumes in several regions, which were also correlated with lower depression symptoms.

They also found that among a large array of metabolic and other markers, the inflammatory protein C-reactive protein (CRP) and triglyceride levels, along with the neutrophil count and total white cell count, were strongly linked to the lifestyle category.

Using structural equation modeling in a small subset of 18,000 individuals, they found that lifestyle affected the depression risk against a background of altered immune and metabolic function and brain structure.

However, the most sizable effect was from lifestyle factors, 3-10-fold higher than that of any other relationship. The polygenic risk score (PRS) was the next in order.

What are the implications?

Our results highlighted the importance of promoting a comprehensive healthy lifestyle for depression intervention.

Zhao et al. (2023)

The study suggested that the greatest impact on depression was from the interaction of multiple healthy lifestyle factors acting through multiple mechanisms. This corroborates earlier studies and is a welcome signal, as these are modifiable risk factors.

Good sleep promotes hippocampus plasticity, while smoking and a poor diet could cause brain lesions, leading to depression.

The number of patients with depression was small in this large cohort. Further research on larger samples may help to describe better how brain structure and immunometabolic markers are related to depression risk.

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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