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MDD is traditionally diagnosed based on a patient\u2019s symptoms, which can lead to misdiagnosis. Although the pathogenic mechanisms of MDD are unknown, several studies have identified mitochondrial dysfunction as a central factor in the onset and progression of MDD. In the context of MDD, alterations in mitochondrial metabolism can lead to imbalances in energy production and oxidative stress, contributing to the disorder\u00b4s underlying pathophysiological mechanisms. Consequently, the identification of mitochondrial dysfunction as a key biomarker for early and accurate diagnosis of MDD represents a significant challenge. Faced with the limits of traditional treatments with antidepressants, new pharmacological therapeutic targets are being investigated such as ketamine\/esketamine, psychedelics, or anti-inflammatories. All of these drugs show potential antidepressant effects due to their speed of action and ability to modulate neuroplasticity and\/or motor processing. In parallel, non-pharmacological therapeutic targets are studied, like Transcranial Magnetic Stimulation (TMS) and Deep Brain Stimulation (DBS), recognized for their ability to modulate neuronal activity and offer treatment alternatives. As cellular activity is directly related to mitochondrial respiration, the aim of this review is examining the link between mitochondrial dysfunction and MDD, assessing how mitochondrial biomarkers could provide a more objective and precise diagnostic tool, and exploring other treatments in addition to traditional antidepressants, with a specific focus on emerging therapeutic targets. Finally, a detailed analysis of the strengths, weaknesses, opportunities, and threats of these approaches was carried out, highlighting the key challenges that must be addressed.<\/jats:p>","DOI":"10.3390\/jcm13061727","type":"journal-article","created":{"date-parts":[[2024,3,18]],"date-time":"2024-03-18T04:25:15Z","timestamp":1710735915000},"page":"1727","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Mitochondrial Metabolism in Major Depressive Disorder: From Early Diagnosis to Emerging Treatment Options"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9231-2233","authenticated-orcid":false,"given":"Ane","family":"Larrea","sequence":"first","affiliation":[{"name":"Research and Development Division, IMG Pharma Biotech, 48170 Zamudio, Spain"},{"name":"Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country UPV\/EHU, 48940 Leioa, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5777-6588","authenticated-orcid":false,"given":"Laura","family":"S\u00e1nchez-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Research and Development Division, IMG Pharma Biotech, 48170 Zamudio, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7151-1639","authenticated-orcid":false,"given":"Eguzki\u00f1e","family":"Diez-Martin","sequence":"additional","affiliation":[{"name":"Research and Development Division, IMG Pharma Biotech, 48170 Zamudio, Spain"},{"name":"Department of Immunology, Microbiology and Parasitology, Faculty of Science and Technology, University of the Basque Country UPV\/EHU, 48940 Leioa, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ane","family":"Elexpe","sequence":"additional","affiliation":[{"name":"Research and Development Division, IMG Pharma Biotech, 48170 Zamudio, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Torrecilla","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country UPV\/EHU, 48940 Leioa, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0338-5554","authenticated-orcid":false,"given":"Egoitz","family":"Astigarraga","sequence":"additional","affiliation":[{"name":"Research and Development Division, IMG Pharma Biotech, 48170 Zamudio, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8330-1567","authenticated-orcid":false,"given":"Gabriel","family":"Barreda-G\u00f3mez","sequence":"additional","affiliation":[{"name":"Research and Development Division, IMG Pharma Biotech, 48170 Zamudio, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"233","DOI":"10.2147\/NDT.S188964","article-title":"Disturbances of Mitochondrial Parameters to Distinguish Patients with Depressive Episode of Bipolar Disorder and Major Depressive Disorder","volume":"15","author":"Raboch","year":"2019","journal-title":"Neuropsychiatr. 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