Glaucoma is associated with damage to the retinal ganglion cells (RGCs) and disrupted circadian rhythms, but melatonin may be able to help. Researchers recently investigated the long-term effects of daily oral melatonin supplements on intraocular pressure (IOP), circadian rhythms, pattern electroretinogram, sleep and mood in patients with stable or advanced primary open-angle glaucoma (POAG).

The team obtained 24-hour records of salivary melatonin and assessed polymorphism of relevant genes. They found that melatonin increased the stability of systemic circadian rhythms by improving phase and IOP alignment. The researchers also reported that melatonin time-dependently decreased IOP and IOP standard deviation.

“The IOP 24-hour mean and IOP standard deviation decreases were more pronounced in individuals with higher initial 24-hour IOP mean,” the researchers noted. “Melatonin improved RGC function in advanced glaucoma, and N95 amplitude increase correlated positively with RGC loss.”

“Damage of inner plexiform layer RGCs presumably impairs photic synchronization and causes circadian rhythm disruption,” the researchers continued. “Evidence for this mechanism was found in recent research…[in which] significant sleep disturbances were inversely correlated with inner plexiform layer RGC functionality and the pupillary light reflex in glaucoma patients. Shorter sleep duration, later sleep phase and delayed body temperature circadian phase correlated with total RGC loss and dysfunction, preceded by lowered systemic circadian rhythm robustness and inter-daily phase stability in mild glaucoma patients compared with controls.”

Patients with advanced glaucoma experienced the most beneficial effects of melatonin on sleep and mood. “Delayed salivary melatonin and systemic phases were observed,” in the genetic profiles of subjects with advanced glaucoma, the investigators added.

In later stages of life, circadian rhythm alterations are normal, and the retina is particularly affected in the aging process. Many neurodegenerative pathologies demonstrate enhanced age-dependent RGC changes as well. Melatonin, a principle chemical factor for detecting environmental light signaling and synchronizing peripheral clocks, serves the input and output of the circadian system, the researchers explained. “Melatonin is regarded as a promising substance to ameliorate complex glaucoma-associated conditions of compromised well-being (i.e., disrupted circadian rhythms, altered sleep and mood).”

The investigators pointed out that currently, high IOP is the only easily manageable factor of RGC loss in glaucoma. “RGC loss in POAG can correlate with phasic changes of the 24-hour IOP rhythm, and misalignment between IOP and systemic circadian phases,” they wrote. “Melatonin can influence IOP by means of both systemic and local mechanisms. A robust circadian rhythm of temperature synchronizes and maintains high-amplitude peripheral circadian rhythms. Melatonin is capable of resynchronizing circadian rhythms of body temperature in the elderly. Exogenously administered melatonin time-dependently modulates blood pressure, with effects that differ between acute vs. chronic intervention. Our present finding that melatonin decreased IOP depending on its 24-hour mean before administration is similar to what we found for blood pressure: a greater reduction associated with initially higher systolic blood pressure values. However, unlike systolic blood pressure, whose greatest reduction after melatonin was achieved between 3 and 8 o’clock in the morning, the greatest IOP reduction was evidenced during later diurnal hours, suggesting that mechanisms of melatonin effects on blood pressure and IOP are partly different.”

The researchers concluded that their results provide evidence for melatonin’s efficiency in restoring disrupted circadian rhythms in glaucoma. “This indicates that a personalized strategy of melatonin administration may further refine its treatment benefits,” they said.

Gubin D, Neroev V, Malishevskaya T, et al. Melatonin mitigates disrupted circadian rhythms, lowers intraocular pressure and improves retinal ganglion cell function in glaucoma. J Pineal Res. March 17, 2021. [Epub ahead of print].