Exploring Associations Between Hypoxia, Serum Erythropoietin, and Cognition in Patients With Mood Disorders and Healthy Individuals.

PURPOSE: Moderate repeated hypoxia (MRH) has shown neuroprotective and neuroplastic effects, partly mediated by erythropoietin (EPO) via hypoxia-inducible factors (HIFs). This study examined the effects of 3 weeks of daily 3.5-h normobaric hypoxia (12% O2) versus normoxia (20% O2) combined with cognitive training on oxygen saturation (SpO2), cerebral side effects, hematology (including EPO and brain-derived neurotrophic factor [BDNF]), and cognitive learning. We also assessed SpO2 associations with side effects, hematology, and learning outcomes, as well as potential clinical and demographic predictors of hypoxic response.

METHOD: Data from 84 healthy participants (HP) and 24 participants with remitted mood disorders (MD) in the ongoing ALTIBRAIN trial (NCT06121206) were analyzed. HP were randomized to MRH or normoxia (with/without cognitive training), while MD participants were randomized to MRH with cognitive training or treatment as usual.

FINDING: MRH reduced SpO2 (97.5% ± 1.0% to 85.9% ± 2.9%, p < 0.001), but this effect attenuated over time (p < 0.001). Side effects (e.g., dizziness and headaches) were slightly higher in MRH (p = 0.044) but declined over time (p < 0.001). Reticulocyte, hemoglobin, and thrombocyte levels increased (p ≤ 0.029), while EPO decreased (p = 0.003) and BDNF remained unchanged (p > 0.60). MRH slightly flattened cognitive learning curves (p < 0.001). MD participants experienced marginally higher side effects (p = 0.006), but overall tolerability was good.

CONCLUSION

MRH was safe and well-tolerated, influencing SpO2, hematology, and learning curves. If future research confirms cognitive and neuroplastic benefits, MRH with cognitive training could be a promising treatment for cognitive impairment.