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In this manuscript, we propose that the metabolic features of bipolar disorder provide a new vector from which to understand the role of circadian dysfunction in this condition. A notable feature of bipolar disorder is the photoperiod driven, seasonal occurrence of symptoms and episodes mediated by circadian systems, with mania occurring more frequently\u00a0in the spring and autumn at times of rapid rate of change in photoperiod, and depression being more prevalent in the winter when photoperiod is attenuated. In this manuscript we note that seasonal adaptations in metabolism are highly conserved evolutionary traits across diverse taxa. Several of the underlying mechanisms mediating seasonal changes in metabolism are conserved in human biology and are implicated in bipolar disorder pathophysiology. Such mechanisms encompass targets of lithium involved in insulin signaling (the phosphatidylinositol cycle, GSK3\u03b2 and Akt), clock genes (CLOCK and BMAL1), targets of psychiatric and metabolic medications (mTOR and AMPK) and hormonal signaling (melatonin and cortisol). We propose that bipolar disorder may represent a dysregulation of conserved mechanisms of chronometabolic regulation and provide a discussion of the evolutionary context of such mechanisms. Genetic predisposition coupled to novel environmental inputs to human biology including artificial light at night and sustained refined sugar and carbohydrate intake may contribute to states of metabolic and circadian dysregulation in bipolar disorder underlying episodes of mania and depression.<\/jats:p>","DOI":"10.1038\/s41380-025-03123-9","type":"journal-article","created":{"date-parts":[[2025,7,19]],"date-time":"2025-07-19T01:28:39Z","timestamp":1752888519000},"page":"5600-5612","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Metabolic plasticity: an evolutionary perspective on metabolic and circadian dysregulation in bipolar disorder"],"prefix":"10.1038","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8756-1326","authenticated-orcid":false,"given":"Iain H.","family":"Campbell","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6997-4215","authenticated-orcid":false,"given":"Mark A.","family":"Frye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,19]]},"reference":[{"key":"3123_CR1","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1192\/bjp.67.278.342","volume":"67","author":"JR Lord","year":"1921","unstructured":"Lord JR. 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