A large-scale study published in Molecular Psychiatry has uncovered a distinct pattern of biological changes in people with major depressive disorder. Individuals experiencing depression, both currently and in the past, showed alterations in various small molecules in their blood, particularly those related to fats. These findings suggest that disruptions in the body’s metabolism, especially concerning fats, may play a significant role in the development and experience of depression, opening new avenues for understanding and potentially treating this widespread condition.
Depression is known to be a multifaceted condition influenced by genetics, environment, and lifestyle. While psychological and social factors are clearly important, researchers are increasingly recognizing that biological processes within the body are also deeply involved. Previous studies exploring the body’s chemistry in relation to depression have often been limited in scope, either focusing on a small number of substances or not involving participants formally diagnosed with depression through thorough psychiatric assessments.
To overcome these limitations and gain a more comprehensive view, researchers aimed to conduct a detailed investigation of a wide range of substances in the blood of a large group of people, including those with current and past depression, as well as healthy individuals, and to repeat these measurements over time. This approach was designed to identify a robust and reliable biological signature associated with major depressive disorder and to explore potential causal links between these biological changes and depression itself.
For their study, the research team utilized data from a large, ongoing Dutch study called the Netherlands Study of Depression and Anxiety. This study has been tracking the mental and physical health of thousands of participants over many years. For this particular analysis, the researchers examined blood samples collected from 2,770 participants at the start of the study. This group included 1,101 people who were experiencing major depressive disorder at the time of the study, 868 people who had experienced depression in the past but were currently in remission, and 801 healthy individuals with no history of depression. Six years later, blood samples were collected again from 1,805 of these participants, allowing for a follow-up analysis.
Participants in the study underwent detailed assessments, including psychiatric interviews to determine if they met the criteria for major depressive disorder according to established diagnostic guidelines. The severity of their depressive symptoms was also measured using a self-report questionnaire that asked about their mood and other symptoms in the week prior to the assessment. In addition to collecting blood samples, the researchers gathered information on various factors that could influence both depression and the substances in the blood. These factors included age, sex, education level, physical activity, smoking and alcohol consumption habits, existing chronic diseases, and medication use, including lipid-lowering drugs and different types of antidepressants.
The blood samples were analyzed using a sophisticated technology that can measure hundreds of different small molecules, known as metabolites, in a single sample. This platform, called Metabolon, allowed the researchers to get a broad overview of the body’s metabolic state. The researchers implemented rigorous quality control procedures to ensure the accuracy and reliability of their metabolite measurements. They then used statistical models to examine the relationships between the levels of these metabolites and depression status (current depression, past depression, or healthy control) and depression symptom severity, while taking into account the various influencing factors they had measured.
To further explore the nature of these relationships, the researchers also employed a technique called Mendelian randomization. This method uses genetic variations as tools to investigate potential cause-and-effect relationships between metabolite levels and depression risk. By leveraging large genetic datasets, they could examine if genetically predicted changes in metabolite levels were associated with a higher or lower risk of developing depression.
The analysis of the initial blood samples revealed that a substantial number of metabolites were different in people with current major depressive disorder compared to healthy controls. Specifically, 139 metabolites showed significant differences. Among these, 92 were found to be at lower levels, while 47 were at higher levels in individuals with current depression.
A large proportion of these altered metabolites, 79 in total, were also associated with the severity of depression symptoms, meaning that the more severe the symptoms, the more pronounced the changes in these metabolites. Interestingly, many of the same metabolites that were altered in people with current depression were also changed in those with past depression, although the changes were generally less pronounced in the remitted group.
Further analysis revealed that a significant portion of the altered metabolites were lipids, or fat-like substances. When the researchers grouped the metabolites into biological pathways, they found that certain pathways related to fats were particularly affected. Metabolites that were found to be decreased in depression were enriched in long-chain monounsaturated and saturated fatty acids, which are types of fats that are important for energy storage and cell structure. Conversely, metabolites that were increased in depression were enriched in lysophospholipids, a class of fats that play roles in cell signaling and inflammation.
To ensure the robustness of their findings, the researchers repeated some of their analyses using the blood samples collected six years later. They were able to confirm 34 of the initially identified metabolites, finding consistent directions of change between the baseline and follow-up measurements. This replication strengthened the evidence that these metabolic alterations are indeed linked to depression.
Finally, using Mendelian randomization, the researchers explored whether any of the identified metabolites might have a causal role in depression. Their analysis suggested that genetically predicted higher levels of a specific lysophospholipid, called 1-linoleoyl-GPE, were associated with an increased risk of depression. This finding provides preliminary evidence that this particular fat-like substance, or the biological processes that control its levels, could potentially contribute to the development of depression.
The researchers acknowledged some limitations to their study. While the follow-up measurements provided some confirmation, it was not a completely independent replication because it involved the same group of people at a later time point. Future studies in entirely new groups of participants are needed to further validate these findings. Additionally, the study design was observational, mainly showing associations rather than definitive proof of cause and effect, except for the preliminary causal evidence from the Mendelian randomization. The participants were also primarily of European ancestry, so it remains to be seen if these findings generalize to other populations.
The study, “The metabolome-wide signature of major depressive disorder,” was authored by Rick Jansen, Yuri Milaneschi, Daniela Schranner, Gabi Kastenmuller, Matthias Arnold, Xianlin Han, Boadie W. Dunlop, the Mood Disorder Precision Medicine Consortium, A. John Rush, Rima Kaddurah-Daouk, and Brenda W. J. H. Penninx.
