Could R‐Ketamine and Wolfram Syndrome Inform Understanding of Depression and Suicidality? A Sigma‐1 Receptor‐Based Perspective
Hans O. Kalkman, L. Smigielski
Human psychopharmacology September 1, 2025 DOI: 10.1002/hup.70019 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Topics | Depression Esketamine Ketamine |
| Key points | Proposes that Wolfram syndrome, a disorder of WFS1 mutations and mitochondrial dysfunction, may serve as a mechanistically informative model for exploring σ1 receptor modulation and affective symptoms. The proposal rests on four arguments, including that R-ketamine selectively binds the σ1 receptor as an agonist, that R-ketamine and other σ1 agonists show antidepressant-like activity in rodents, and that R-ketamine may carry lower abuse potential and fewer side effects than S-ketamine. |
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.
Comparable studies
Other theoretical and historical papers on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| An Integrative Approach to Ketamine Therapy May Enhance Multiple Dimensions of Efficacy: Improving Therapeutic Outcomes With Treatment Resistant Depression. | 2021 | Theoretical or philosophical paper | |
| Arketamine for cognitive impairment in psychiatric disorders | 2023 | Theoretical or philosophical paper | |
| The Montreal model: an integrative biomedical-psychedelic approach to ketamine for severe treatment-resistant depression | 2023 | Theoretical or philosophical paper | |
| Ketamine in Bipolar Disorder: A Review | 2020 | Theoretical or philosophical paper | |
| Rethinking the role of TRKB in the action of antidepressants and psychedelics. | 2024 | Theoretical or philosophical paper |
Citations in the library
Cites 27
- The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis American Journal of Psychiatry October 3, 2017
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
- Double-Blind, Placebo-Controlled, Dose-Ranging Trial of Intravenous Ketamine as Adjunctive Therapy in Treatment-Resistant Depression (TRD) Molecular Psychiatry October 3, 2018
- Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis Journal of Affective Disorders September 23, 2020
- EFFECTS OF KETAMINE ON EXPLICIT AND IMPLICIT SUICIDAL COGNITION: A RANDOMIZED CONTROLLED TRIAL IN TREATMENT-RESISTANT DEPRESSION Depression and Anxiety March 25, 2014
and 22 more in the library