Could R-Ketamine and Wolfram Syndrome Inform Understanding of Depression and Suicidality? A Sigma-1 Receptor-Based Perspective

Abstract

Loss of function mutations in the WFS1 gene cause Wolfram syndrome, which is characterized by juvenile-onset diabetes mellitus, diabetes insipidus, neurodegeneration, hearing loss and optic nerve atrophy. Psychiatric symptoms, including major depression and suicidal behavior, are common in this disorder. WFS1 mutations induce this condition through altering interactions between the endoplasmic reticulum and mitochondria, resulting in diminished Ca²⁺ import that leads to mitochondrial dysfunction. Quite recently, it was shown that such impaired Ca²⁺ transport could be restored by the experimental σ1 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 σ1 receptor modulation, mitochondrial dysfunction, and affective symptoms. This proposal is based on four arguments. Firstly, the R-enantiomer of ketamine exhibits largely selective binding to the σ1 receptor as an agonist. Secondly, R-ketamine and other σ1 agonists display antidepressant-like activity in rodent depression models. Thirdly, while both S- and R-ketamine 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.