Metabolomics and Proteomics in Major Depressive Disorder

Major depressive disorder (MDD) is characterised by complex molecular perturbations that span neurotransmitter balance, energy metabolism, lipid signalling and immune modulation. Metabolomics and proteomics offer complementary lenses for capturing these alterations at the level of small molecules and proteins, respectively. High-resolution mass spectrometry and nuclear magnetic resonance enable the unbiased profiling of hundreds to thousands of metabolites and protein species in brain tissue, biofluids and animal models. Integrative analyses have revealed consistent dysregulation of amino acid metabolism (notably the tryptophan–kynurenine pathway), fatty acid composition, neurotransmitter intermediates and synaptic signalling proteins. Proteomic studies in key regions such as the hippocampus point to aberrant expression of kinases, synaptic scaffolds and mitochondrial enzymes within AKT and MAPK networks. Peripheral metabolite signatures in blood and urine hold promise as objective diagnostic or prognostic biomarkers, while tissue-based profiles illuminate potential therapeutic targets. Collectively, this body of work underscores the global significance of biochemical phenotyping in understanding MDD heterogeneity and guiding personalised interventions.

Research from Nature Portfolio

Metabolomics was applied to a chronic mild stress mouse model treated with two widely used antidepressants, fluoxetine and imipramine. Untargeted gas chromatography–mass spectrometry of hippocampal extracts identified 23 differentially expressed metabolites linked to amino acid, energy and neurotransmitter pathways. Notably, myo-inositol emerged as a potential marker of fluoxetine response, while lysine and oleic acid distinguished imipramine treatment effects. This study illustrates how global metabolic profiling can elucidate antidepressant mechanisms and pinpoint candidate biomarkers for monitoring therapeutic efficacy.

Metabolomics and Proteomics in Major Depressive Disorder publication trend

The graph below shows the total number of articles in metabolomics and proteomics in major depressive disorder across all publications each year (not limited to Nature Index journals).

Technical terms

Metabolomics: The comprehensive analysis of small-molecule metabolites in biological samples to map biochemical changes associated with disease states.

Proteomics: The large-scale study of the structure, function and interactions of proteins expressed in a cell, tissue or organism.

Mass spectrometry: An analytical technique that measures the mass-to-charge ratio of ions, enabling identification and quantification of metabolites and proteins in complex mixtures.

AKT and MAPK signalling pathways: Intracellular protein kinase cascades regulating cell survival, growth and synaptic plasticity, implicated in stress response and depression.

Tryptophan–kynurenine pathway: A metabolic route converting tryptophan to kynurenine and downstream metabolites, linked to neuroactive compound balance and immune modulation in MDD.

References

1. Metabolomic identification of biochemical changes induced by fluoxetine and imipramine in a chronic mild stress mouse model of depression. Scientific Reports (2015).
2. AKT and MAPK signaling pathways in hippocampus reveals the pathogenesis of depression in four stress-induced models. Translational Psychiatry (2023).
3. An integrated meta-analysis of peripheral blood metabolites and biological functions in major depressive disorder. Molecular Psychiatry (2020).
4. Diagnosis of major depressive disorder based on changes in multiple plasma neurotransmitters: a targeted metabolomics study. Translational Psychiatry (2018).