Large-scale research published in Molecular Psychiatry It uncovered clear patterns of biological changes in people with major depressive disorders. Individuals experiencing depression both present and past showed changes in a variety of small molecules in the blood, particularly those associated with fat. These findings suggest that disruptions in the body’s metabolism, particularly regarding fat, can play an important role in the development and experience of depression, paving new avenues for understanding and potentially treating this broad condition.
Depression is known to be a multifaceted condition affected by genetics, environment and lifestyle. Psychological and social factors are obviously important, but researchers are increasingly aware that biological processes within the body are also deeply involved. Previous studies investigating body chemistry related to depression often focus on a minority range or do not involve participants who have been formally diagnosed with depression through a thorough psychiatric assessment.
To overcome these limitations and gain a more comprehensive view, the researchers aimed to conduct a detailed investigation of a wide range of substances in the blood of large groups including current and past depression, as well as healthy individuals, with the aim of repeating these measurements over time. This approach was designed to identify robust and reliable biological features associated with major depressive disorders and to investigate the potential causal relationship between these biological changes and the depression itself.
For their research, the researchers utilized data from a large, ongoing Dutch study called the Dutch Study on Depression and Anxiety. The study has tracked the mental and physical health of thousands of participants over the years. For this particular analysis, the researchers looked at blood samples collected from 2,770 participants at the start of the study. This group included 1,101 people who had experienced major depression disorder at the time of the study, 868 people who had previously experienced depression but were in remission, and 801 people who had no history of depression. Six years later, blood samples were collected again from 1,805 of these participants, allowing for follow-up analysis.
Participants in this study underwent a detailed assessment, including psychiatric interviews, to determine whether they met criteria for major depressive disorder according to established diagnostic guidelines. The severity of their depressive symptoms was measured using a self-report questionnaire asking about their mood and other symptoms the week before the assessment. In addition to collecting blood samples, researchers gathered information on a variety of factors that could affect both depression and substances in the blood. These factors include drug use such as age, gender, education level, physical activity, smoking and alcohol consumption habits, existing chronic diseases, lipid-lowering drugs, and various types of antidepressants.
Blood samples were analyzed using sophisticated techniques that allow hundreds of different small molecules known as metabolites in a single sample. The platform, called Metabolon, allowed researchers to obtain a broad overview of the body’s metabolic state. Researchers implemented strict quality control procedures to ensure the accuracy and reliability of metabolite measurements. Statistical models were then used to examine the relationship between the levels of these metabolites and the status of depression (current depression, past depression, or healthy controls) and the severity of depressive symptoms, and considered the various influential factors measured.
To further explore the nature of these relationships, the researchers also adopted a technique called Mendel’s randomization. This method uses genetic variation as a tool to investigate the relationship between potential causes and effects between metabolite levels and depression risk. By leveraging a large genetic dataset, we were able to investigate whether genetically predicted changes in metabolite levels are associated with higher or lower risk of developing depression.
Analysis of the initial blood samples revealed a considerable number of metabolites differed in people with current major depressive disorders compared to healthy controls. Specifically, 139 metabolites showed significant differences. Of these, 92 were found to be at lower levels, while 47 was at higher levels in current individuals with depression.
A total of 79 of these altered metabolites were associated with the severity of depressive symptoms, meaning the more severe the symptoms, the more pronounced the changes in these metabolites. Interestingly, many of the same metabolites that changed in people with current depression also changed in people with past depression, but the changes were not generally noticeable in the remitted groups.
Further analysis revealed that a significant portion of the modified metabolites are lipids or fat-like substances. When researchers grouped metabolites into biological pathways, they found that certain pathways associated with fat are particularly affected. Metabolites found to be reduced in depression were concentrated with long chain monosaturated fatty acids, a type of fat that is important for energy storage and cell structure. Conversely, metabolites increased in depression were concentrated with lyson phospholipids, a class of fats that play a role in cell signaling and inflammation.
To ensure robustness of the findings, researchers repeated some of the analysis using blood samples collected six years later. They were able to confirm 34 of the metabolites initially identified, finding a consistent orientation of change between baseline and follow-up measurements. This replication strengthened evidence that these metabolic changes were indeed associated with depression.
Finally, using Mendel’s randomization, the researchers investigated whether any of the identified metabolites may have a causal role in depression. Their analysis suggests that genetically predicting higher levels of a particular lysophospholipid called 1-linoleyl-GPE is associated with an increased risk of depression. This finding provides preliminary evidence that this particular fat-like substance, or the biological process that controls its levels, may potentially contribute to the development of depression.
The researchers acknowledged some limitations on their research. The follow-up measurement provided some confirmations, but it was not a completely independent replicate as the same group of people was involved at a later time. Future research from a whole new group of participants is needed to further examine these findings. Furthermore, the study design was observational and showed a relationship, primarily rather than conclusive evidence of cause and effect, except for preliminary causal evidence from Mendel’s randomization. Participants were also primarily European ancestors, so it remains to be seen whether these findings have been generalized to other populations.
the study, “Signature of the entire metabolome of major depressive disorderRick Jansen, Yuri Milaneski, Daniela Schlanner, Gabi Kastenmaller, Matthias Arnold, Xianlin Han, Boadie W. Dunlop, The Mood Dission Precision Medicine Consortium, A. Written by John Rush, Rima Kaddurah-Daouk, and Brenda Wjh Penninx.
