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.

1. Background

1.1. Wolfram Syndrome

Wolfram syndrome is a rare autosomal recessive disorder affecting the brain and multiple other organs (Caruso et al. 2024; Kõks 2023). Its pathology is characterized by juvenile‐onset diabetes mellitus, diabetes insipidus, neurodegeneration, hearing loss and optic nerve atrophy (Chaussenot et al. 2011; R. G. Swift et al. 1990). Additionally, individuals who are affected by Wolfram syndrome often present an increased risk of psychiatric disorders, particularly depression and suicidal behavior (Cryns et al. 2003; Koido et al. 2005; Mirfazeli et al. 2022; Sequeira et al. 2003; R. G. Swift et al. 1990). Carriers of the WS gene were found to be 26 times more likely to require psychiatric hospitalization than non‐carriers, and the incidence of suicide‐related behaviors in Wolfram syndrome was found to be high, reaching 25% (R. G. Swift et al. 1998). In addition, the relative risk of psychiatric hospitalization due to depression was estimated at 7.1 (M. Swift and Swift 2005). Furthermore, the disease causes significant early‐stage brain abnormalities (Hershey et al. 2012) and later neurodegenerative effects (Rigoli et al. 2018) involving mechanisms known to contribute to the development of psychiatric disorders (Cagalinec et al. 2016; Hao et al. 2023). Overall, this suggests that while affective symptoms in Wolfram syndrome may in part reflect the burden of medical illness, they could also be linked to mechanisms that are driven by the syndrome's core pathophysiological features.

Wolfram syndrome is caused by mutations in WFS1, a gene that encodes the glycoprotein wolframin (Crouzier et al. 2022). Wolframin is localized to particular areas of the endoplasmic reticulum (ER) that interact with mitochondria, which are referred to as mitochondria‐associated ER membranes (MAMs) (Crouzier et al. 2022). Within MAMs, wolframin interacts with two MAM‐resident proteins: neuronal Ca²⁺ sensor‐1 (NCS1) and inositol‐triphosphate‐receptor‐1 (IP3R1) (Angebault et al. 2018). Wolframin is furthermore known to interact with voltage‐dependent anion channel‐1 (VDAC1), a protein that is located in the outer leaflet of the mitochondrial membrane (Zatyka et al. 2023). Mutations in WFS1 affect protein stability (Kõks 2023) and diminish IP3R‐VDAC1 dependent Ca²⁺ trafficking between the ER and the mitochondrial matrix (Angebault et al. 2018; Delprat et al. 2018; Liiv et al. 2024). This has severe functional consequences, including mitochondrial dysfunction, reduced ATP production, increased production of reactive oxygen radicals and increased apoptotic cell death (Crouzier et al. 2022; Zatyka et al. 2023). Mitochondrial dysfunction and its pro‐apoptotic consequences provide a plausible explanation for general neurodegeneration, the loss of optic, acoustic and hypothalamic vasopressin neurons, as well as the destruction of pancreatic β‐cells. Reactive oxygen species are known to activate c‐JUN N‐terminal kinase (JNK), which inhibits the insulin‐signal transduction, thereby contributing to insulin resistance and the development of type 2 diabetes (Aguirre et al. 2002; Yin et al. 2013). Furthermore, major depression is associated—and possibly caused by—mitochondrial dysfunction (Allen et al. 2021; Bansal and Kuhad 2016; Cardon et al. 2024). The pathophysiological process underlying suicide, however, remains largely unknown. This is partly due to the inability to model suicide in animal studies, and the low incidence of fatal suicide (even in psychiatric populations). As a nearly monogenetic disorder (Caruso et al. 2024), Wolfram syndrome may offer unique insight in the pathophysiology of suicide and, potentially, severe depression. Given the urgent need for a deeper understanding of suicide, the notably high incidence of suicide in Wolfram syndrome may provide insights into the biological mechanisms underlying suicidality. There is currently no specific treatment for the metabolic and CNS pathologies associated with WFS1 mutations (Caruso et al. 2024; Kõks 2023).

1.2. Wolframin Interacts With NCS1 and σ1 Receptors

Quite recently, Crouzier and colleagues reported that the experimental compound PRE084, a selective agonist of σ1 receptors (Motawe et al. 2020), restored mitochondrial respiration and alleviated behavioral symptoms in animal models of Wolfram syndrome (Crouzier et al. 2022). The σ1 receptor is a small, ligand‐regulated chaperone protein (Ossa et al. 2017; Szabo et al. 2016) that modulates cellular Ca²⁺ homeostasis through interactions with several ligand‐ and voltage‐gated ion channels, including IP3R (Hayashi and Su 2007; Schmidt and Kruse 2019). Moreover, σ1 receptors are densely clustered within MAMs (Hayashi and Su 2003), and upon ligand binding, they potentiate Ca²⁺ flux from the ER to mitochondria (Hayashi 2019; Ossa et al. 2017; Szabo et al. 2016). After entry into the mitochondrion, Ca²⁺ drives the Krebs cycle, boosts the mitochondrial respiratory chain and thus raises ATP production (Bonora et al. 2012; Patergnani et al. 2014). Notably, the identity of the endogenous ligand of the σ1 receptor remains unclear (Pergolizzi et al. 2023). Proposed candidates include choline, neuro‐steroids, dimethyltryptamines, myristic acid and sphingolipids (Brailoiu et al. 2019; Fu et al. 2024; Szabo et al. 2016). In the central nervous system, σ1 receptors are expressed by neurons, microglia, astrocytes and oligodendrocytes (Nguyen et al. 2015).

As noted, at ER–mitochondrion interfaces, wolframin forms a complex with NCS1, IP3R and VDAC1 to promote Ca²⁺ transfer between the ER and mitochondria (Angebault et al. 2018; Zatyka et al. 2023). The point of convergence between the proteins that interact with wolframin and with σ1 receptors is NCS1. In Neuro2A cells, σ1 receptors coprecipitated with NCS1 and more faintly also with wolframin (Crouzier et al. 2022). In fibroblasts from patients with Wolfram syndrome, the expression of NCS1 in MAMs was reduced, whereas overexpression of NCS1 or activation of σ1 receptors restored the diminished Ca²⁺ transfer and its functional consequences (Crouzier et al. 2022). Contrary to its name, NCS1 is expressed beyond neurons (and fibroblasts), as it is also expressed by cardiomyocytes, pancreatic β‐cells, retinal ganglion cells (summarized in Angebault et al. 2018), neuroendocrine cells, mast cells, neutrophils, lymphocytes and monocytes (Torres et al. 2009), as well as in different cancer cell lines (Sánchez et al. 2024). As a putative indicator of MAM dysfunction, altered expression of NCS1 was reported in tissues from patients with bipolar disorder and schizophrenia (Koh et al. 2003; Torres et al. 2009).

Whilst selective agonists for the σ1 receptor are under clinical development (Malar et al. 2023), only a few have reached the clinical research stage and none have entered the market (Crouzier et al. 2022). Nevertheless, several medications, including donepezil, rivastigmine, fenfluramine, fluoxetine, fluvoxamine, ketamine and memantine, display, in addition to their targeted pharmacological activity, a relevant σ1 agonist effect (Malar et al. 2023; Robson et al. 2012). Such compounds could serve as pharmacological tools for pilot studies in human subjects.

2. Ketamine's R‐Enantiomer Displays Significant Affinity for σ1 Receptors

Ketamine is a rapidly acting antidepressant compound with efficacy in treatment‐resistant depression (Alnefeesi et al. 2022; Bahji et al. 2021; Bentley et al. 2022; Fava et al. 2020; Marcantoni et al. 2020). There is also a rich literature indicating that ketamine effectively reduces suicidal behavior (Averill et al. 2022; Ballard et al. 2014; Feeney et al. 2021; Price et al. 2014; Wilkinson et al. 2018). Ketamine is a racemate. S‐ketamine blocks ion transport through the NMDA‐type glutamate‐gated ion channel and acts as a partial agonist activity of opioid μ‐receptors (Bonaventura et al. 2021). Alongside the widely studied S‐ketamine in clinical settings, the less‐researched R‐enantiomer of ketamine (also known as arketamine) is emerging as a potential alternative for treatment‐resistant depression (Scotton et al. 2022). In animal studies, R‐ketamine demonstrated higher potency and more prolonged antidepressant effects compared to S‐ketamine (Fukumoto et al. 2017; J. C. Zhang et al. 2014). In humans, limited small studies have observed a rapid antidepressant effect of R‐ketamine infusions in treatment‐resistant depressive patients (Leal et al. 2021), with benefits extending over longer follow‐up periods (Włodarczyk et al. 2024). However, a subsequent small placebo‐controlled study by the same group (n = 10) did not demonstrate superiority of R‐ketamine over placebo, and larger confirmatory trials are still lacking (Johnston et al. 2023). Unpublished results from a 2023 Phase 2a trial showed no statistically significant difference in depressive symptoms between R‐ketamine (30 and 60 mg) and placebo at the 24‐h primary endpoint, though numerically greater response and remission rates were observed in the 60 mg arm over 2 weeks (Atai Life Sciences 2023, press release). In light of this still limited human evidence, our discussion of R‐ketamine is framed within a hypothesis‐generating and mechanistic context, not as a therapeutic recommendation.

Additionally, R‐ketamine, in contrast to S‐ketamine, does not profoundly induce psychotomimetic effects (Hashimoto 2020; Vollenweider et al. 1997) or dissociation (Leal et al. 2021) and is likely to have a lower potential for abuse (Chang et al. 2019). Both S‐ and R‐ketamine hold the potential as rapid antisuicidal agents (Dadiomov and Lee 2019). However, distinctions between these two enantiomers may produce different outcomes in terms of their effects on suicidality. Of note, the effects of R‐ketamine are mediated via activation of the extracellular signal‐regulated kinase (ERK) pathway, whereas the effects of S‐ketamine are mediated through disinhibition of mechanistic target of rapamycin complex 1 (mTORC1) signaling (Kang et al. 2022; Yang et al. 2015). Notably, R‐ketamine displays significant affinity for σ1 receptors (Bonaventura et al. 2021; Hustveit et al. 1995), whereas it lacks relevant affinity to other receptor binding sites (Bonaventura et al. 2021). Presumably, R‐ketamine is a σ1 agonist, as in a drug‐discrimination study the ketamine‐induced drug cue was inhibited by a σ1 receptor antagonist (Narita et al. 2001). Moreover, in some preclinical depression models, the antidepressant‐like responses of ketamine were blocked by σ1 receptor antagonists (Ma et al. 2024; Robson et al. 2012).

3. σ1 Receptors at the Crossroads of Metabolic and Psychiatric Dysregulation

The signaling process by which mutated WFS1 proteins give rise to diabetes or to depressive and suicidal behaviors remains to be detailed, but most likely involves mitochondrial dysfunction caused by reduced Ca²⁺ transport and altered interactions between the ER and mitochondria in pancreatic β‐cells and neurons, respectively (Angebault et al. 2018). Data from Crouzier et al. (2022) provide the critical insight that impaired Ca²⁺ transport across the MAMs can be rescued by PRE084, an agonist of σ1 receptors. Since functional mitochondria are essential for both cellular function and survival, it is unsurprising that the activation of σ1 receptors has been proposed as a potential treatment for behavioral/psychiatric disorders (Ren et al. 2022; Salaciak and Pytka 2022; Voronin et al. 2020; Y. M. Wang et al. 2022) and neurological/neurodegenerative disorders (Herrando‐Grabulosa et al. 2021; Malar et al. 2023; Weng et al. 2017). R‐ketamine seems to be a selective σ1 agonist, and in preclinical studies, R‐ketamine indeed displayed antidepressant‐like activity (Hashimoto 2020; J. Zhang et al. 2021; Johnston et al. 2023). However, clinical confirmation that R‐ketamine possesses antidepressant activity remains lacking; in contrast, the anti‐depressant effect of S‐ketamine has been clearly established (Chen et al. 2023; Correia‐Melo et al. 2020; Singh et al. 2023; Takahashi et al. 2021). Whether stimulation of σ1 receptors reduces insulin resistance has not been investigated in humans or even in animal models. Since σ1 agonists improve mitochondrial function and presumably reduce the production of reactive oxygen radicals (Goguadze et al. 2019; Oxombre et al. 2015), it is possible that σ1 agonists counteract insulin‐resistance by restoring insulin‐induced signal transduction.

In this context, it is worth noting that the antidepressant effect of racemic ketamine was relatively greater both in patients with a high versus low body mass index (BMI) (Freeman et al. 2020) and in those with low versus high adiponectin levels (Machado‐Vieira et al. 2017). Both high BMI values and low adiponectin levels are indicators of type 2 diabetes and thus insulin resistance (Hotta et al. 2001; Kopp et al. 2005; Y. Wang et al. 2018). This observation is consistent with data from an animal study in which the SSRI/σ1 agonist fluvoxamine inhibited depression‐like behavior in streptozotocin‐induced diabetic rats, an effect that was blocked by a σ1 antagonist (Lenart et al. 2016). Patients with depression and suicidal behavior were reported to exhibit higher blood glucose concentrations than depressed patients without suicidal behavior, and glucose levels were found to correlate with the prevalence of suicidal behavior (Koponen et al. 2015). Similarly, patients who had made violent suicide attempt showed higher CSF insulin levels than those with nonviolent attempts (Westling et al. 2004), as well as elevated plasma and CSF insulin levels compared to healthy controls (Bendix et al. 2017). These results point to a role of insulin resistance in suicidal behavior, which may, in some cases, be independent of depression (Westling et al. 2004).

4. Future Directions

Based on the aforementioned circumstantial evidence, clinicians could reasonably consider fluvoxamine treatment of patients with Wolfram syndrome and its associated psychiatric symptoms. However, it remains unclear if the target therapeutic effect would be caused by 5‐HT uptake inhibition or σ1 stimulation. Wolfram syndrome also provides a valuable model to investigate the therapeutic potential of repairing mitochondrial dysfunction, possibly mediated by sigma‐1 receptor pathways. While clinical application is premature at this stage, exploratory studies with R‐ketamine in patients with Wolfram syndrome could help to partially elucidate these mechanisms and generate further hypotheses. Given the severity and lethality of Wolfram syndrome (Kinsley et al. 1995), and the absence of effective treatments, such exploratory investigations may be justified and hold translational potential. This line of research also has the potential to elucidate other indications in which σ1 stimulation and downstream pathways may be of therapeutic value. It should be noted that other compounds are also of interest in Wolfram syndrome. Dantrolene, an ER calcium stabilizer, has been shown to reduce ER stress and prevent cell death in WFS1‐deficient iPSC‐derived neural progenitor cells (Lu et al. 2014), and has demonstrated safety and potential benefit in a Phase Ib/IIa clinical trial (Abreu et al. 2021). Valproic acid, a mood stabilizer that induces p21 and WFS1 expression, confers protection against cell death, modulates ER stress, and prevents aberrant axon guidance and neurite outgrowth defects (Gharanei et al. 2013; Kakiuchi et al. 2009; Pourtoy‐Brasselet et al. 2021), and is currently under investigation in a Phase 2 clinical trial (NCT03717909; Dias et al. 2025). GLP‐1 receptor agonists have also been shown to alleviate ER stress, support β‐cell survival, and reduce neurodegeneration in rodent and human preclinical models of Wolfram syndrome (Gorgogietas et al. 2023; Kondo et al. 2018; Seppa et al. 2019).

Conflicts of Interest

The authors declare no conflicts of interest.

Kalkman, Hans O. , and Smigielski Lukasz. 2025. Could R‐Ketamine and Wolfram Syndrome Inform Understanding of Depression and Suicidality? A Sigma‐1 Receptor‐Based Perspective Human Psychopharmacology: Clinical and Experimental: e70019. 10.1002/hup.70019.

Data Availability Statement

Data sharing is not applicable, as no datasets were generated or analyzed in the preparation of this article.