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Psychiatric symptoms, including major depression and suicidal behavior, are common in this disorder. <jats:italic>WFS1<\/jats:italic> mutations induce this condition through altering interactions between the endoplasmic reticulum and mitochondria, resulting in diminished Ca<jats:sup>2+<\/jats:sup> import that leads to mitochondrial dysfunction. Quite recently, it was shown that such impaired Ca<jats:sup>2+<\/jats:sup> transport could be restored by the experimental \u03c31 receptor agonist PRE084. In animal models of Wolfram syndrome, this compound restored the behavioral phenotype. Based on these previous data, we propose that Wolfram syndrome may serve as a mechanistically informative model for exploring \u03c31 receptor modulation, mitochondrial dysfunction, and affective symptoms. This proposal is based on four arguments. Firstly, the R\u2010enantiomer of ketamine exhibits largely selective binding to the \u03c31 receptor as an agonist. Secondly, R\u2010ketamine and other \u03c31 agonists display antidepressant\u2010like activity in rodent depression models. Thirdly, while both S\u2010 and R\u2010ketamine hold potential for reducing suicidal behavior, the latter is likely to have a lower potential for abuse and fewer side effects. Fourth, Wolfram syndrome is characterized by mitochondrial dysfunction, which has also been linked to depression.<\/jats:p>","DOI":"10.1002\/hup.70019","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T07:51:42Z","timestamp":1758009102000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Could R\u2010Ketamine and Wolfram Syndrome Inform Understanding of Depression and Suicidality? 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