How important is inflammation and body weight in the origin of depression?

Depression, properly termed major depressive disorder (MDD), is a major player on the world disease stage. Usually treated by antidepressants and psychotherapy, it may sometimes become treatment-resistant depression (TRD).

A new paper in BMC Medicine examines the role of inflammation and body mass index (BMI) in the etiology of treatment-resistant depression.

Body mass index and inflammation in depression and treatment-resistant depression: a Mendelian randomisation study
Study: Body mass index and inflammation in depression and treatment-resistant depression: a Mendelian randomisation study. Image Credit: chaipong pramjit/


Chronic disability is linked to depression in a large proportion of cases, with MDD being the third or higher on the list of causes of disability. Treatment-resistant depressionis diagnosed in about 7% of MDD cases. The further management of these patients will rely on understanding why they are resistant to standard treatment.

A high BMI has been reported to put the individual at risk for MDD, perhaps by reducing the level of physical health and thus lowering the mood. In fact, this association of BMI with subsequent depression was observed in over a quarter of cases. The greater the BMI, the more likely the individual is to develop MDD later.

Negative social reactions to obesity and overweight may explain part of this association. MDD occurs later in life, sparing children or adolescents. Also, obesity is linked to depression risk irrespective of metabolic consequences unfavorable to health, which seems to support the social hypothesis. Weight loss management is also linked to reduced depressive symptoms.

The presence of an inflammatory state in obesity is also a topic of investigation. CRP is a liver protein synthesized during inflammation, but its role as a driver of disease is controversial. However, it is an accepted biomarker of disease progression in autoimmune and infectious diseases.

The study used the Mendelian randomization (MR) approach. This is an epidemiological research method that tests associations of genetic variables, usually single nucleotide polymorphisms (SNPs), that predict an exposure of interest such as CRP in this study, with the outcome of interest, that is, TRD.

This avoids the confounding effect of other factors that could alter the CRP value such as smoking, BMI or autoimmune disease, allowing causal associations to be identified.

It is still subject to pleiotropic errors, whereby the SNP affects the outcome but not through the exposure being studied. To avoid this, multivariable MR (MVMR) studies are conducted to identify the causal effects of an exposure that depends on a bigger set of genetically predicted exposures.

MVMR has shown that the CRP rises with increasing BMI. The researchers used MR to examine how inflammation and the body mass index (BMI) contribute to the occurrence of depression.

The data for this study came from the UK Biobank, specifically from a cohort of over 450,000 people, utilizing their mental health and clinical records. The investigators determined the presence of TRD from primary care records and prescriptions.

Multiple MR techniques were used to ensure the validity of the final analyses. They also used a customized statistical technique enabling them to use MR on one-sample data.

What did the study show?

Observational correlations linked treatment-resistant depression to higher CRP and BMI compared to either MDD patients or healthy people. However, the CRP levels were not consistent with active inflammation, though people with MDD or TRD had higher levels than controls. Females comprise a higher proportion of MDD and TRD cohorts.

The findings from univariable MR modeling showed that the risk of depression and TRD were raised with genetic risk for a high BMI. For an increase in the genetically predicted BMI by 1 standard deviation (1 SD), the lifetime risk of being diagnosed with MDD rose by 14%.

The odds of being diagnosed with MDD by a general practitioner (GP) rose by almost a fifth, while those of TRD were 42% higher.

This effect was larger in females, except in the association with TRD, while in males, a rising BMI was associated only with increasing severity of depression. The association was muted with advancing age.

Univariable MR indicated that a 1 SD rise in genetically predicted CRP levels increased the odds of a lifetime diagnosis of depression by 13%, a GP diagnosis of depression by a fifth, and TRD odds by two-thirds, compared to those with low CRP levels. These effects were lost, however, in the MVMR analyses combining genetically predicted BMI and CRP levels.

These indicated that the presence of inflammation led to more severe depression partly because of the association of the former with higher BMI values. The contribution of the BMI to TRD was independent of inflammation, confirming earlier hypotheses.

This could support a role for social contribution to the risk for depression, independent of the metabolic or inflammatory effects of a high BMI.

What are the implications?

The researchers inferred that “BMI exerts a causal effect on depression phenotypes, with the effect being stronger in females and in younger individuals.” This effect is not related to CRP levels, which become non-significant in their association with treatment-resistant depression when combined with the BMI.

This corroborates and supports earlier studies that indicate a contributory role of obesity in depression even without overt metabolic disease. TRD patients are likely to have a large contribution from obesity even after compensating for the role of obesity in triggering MDD. Apart from the social impact, inflammation does not seem to mediate the role of BMI in depression, but this cannot be definitively concluded without more specific studies on inflammatory mediators.

Reducing the BMI may improve mood especially in women and younger people.

Overall, we [recognize] that in the care for MDD, other factors and psychological suffering take precedence and it is important to [prioritize] interventions.

Karageorgiou et al. (2023)

Future studies should focus on more specific aspects of obesity-related metabolic dysfunction and inflammation, as well as bias due to heritable influences on the BMI-depression association, such as assortative mating.