Causal Links Between Cerebrospinal Fluid Metabolites and Postpartum Depression: A Bidirectional Mendelian Randomization Study

Background: Postpartum depression (PPD) significantly affects maternal health and infant development, yet its underlying neurochemical mechanisms remain poorly understood. While observational studies have linked cerebrospinal fluid (CSF) metabolites with mood disorders, causal relationships are difficult to establish due to confounding environmental factors. Methods: We applied bidirectional two-sample Mendelian randomization (MR) to explore causal associations between 338 CSF metabolites and PPD. Genetic instruments were obtained from a metabolome-wide GWAS (n=291), and PPD summary statistics were derived from the FinnGen study (7604 PPD cases; 59,601 controls). Forward MR assessed how CSF metabolites affect PPD risk, while reverse MR evaluated the impact of PPD on metabolite levels. The primary analysis used inverse-variance weighting (IVW), supported by MR-Egger, weighted median/mode, and sensitivity tests including Cochran’s Q and MR-PRESSO. Results: Forward MR identified 10 CSF metabolites with causal effects on PPD. Protective metabolites included guanosine, argininosuccinate, maleate, N6-methyllysine, and homocarnosine. In contrast, increased levels of N-acetyl-isoputreanine, glucose, benzoate, gluconate, and arachidonate were associated with higher PPD risk. Reverse MR showed that PPD may causally lower CSF maleate levels, suggesting mitochondrial involvement in disease progression. All findings were robust to sensitivity analyses, with no evidence of pleiotropy. Conclusion: This study is the first to use bidirectional MR to investigate the causal role of CSF metabolites in PPD. Our results highlight potential metabolic drivers and feedback mechanisms in PPD, especially the reciprocal link with maleate. These findings offer new insights into PPD’s neurobiology and suggest novel targets for early detection and may inform novel therapeutic strategies in maternal mental health. Plain Language Summary: Postpartum depression (PPD) is a serious condition that affects both the mother’s mental health and the baby’s development. Some certain chemicals in cerebrospinal fluid (CSF) may be linked to depression, but it’s hard to tell whether those chemicals actually cause the depression or are just a result of it. In this study, researchers used a method called Mendelian randomization, which uses genetic data to understand cause-and-effect relationships. We looked at genetic information from thousands of people to find out whether specific substances found in the fluid around the brain play a role in PPD. The study found that 10 different CSF chemicals may affect the risk of developing PPD. Some, like guanosine and maleate, seem to help protect against depression. Others, like glucose and benzoate, may increase the risk. Interestingly, they also found that PPD itself may lower levels of maleate, which could be a sign of problems in the cells’ energy production. These findings suggest that certain CSF chemicals could be both causes and consequences of PPD. This opens the door to developing new ways to detect or treat PPD earlier, perhaps by targeting these chemicals. Keywords: postpartum depression, cerebrospinal fluid metabolites, mendelian randomization