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Keywords:

  • circadian system;
  • depression;
  • glaucoma;
  • melatonin;
  • retinal ganglion cells

Abstract

  1. Top of page
  2. Abstract
  3. Background
  4. Method
  5. Melatonin regulation of the circadian system
  6. Circadian misalignment in ophthalmic diseases
  7. Retinal ganglion cell degeneration in glaucoma
  8. Involvement of melatonin in the pathophysiology of glaucoma
  9. The role of melatonin in depression
  10. Summary and clinical implications
  11. Conclusion
  12. References

Abstract:  Glaucoma is a frequent ophthalmologic condition leading to chronic progressive optic neuropathy, which can result in visual impairment and blindness. In addition, glaucoma is associated with a dysregulation of circadian rhythms, as well as with a high incidence of sleep disorders, depression, and anxiety. However, because of their high comorbidity in older age, these conditions have not received much scientific attention and are often undertreated. In the current paper, we review the available literature on the role of melatonergic mechanisms in glaucoma, regulation of circadian rhythms, and depression. The literature is presented as a narrative review, providing an overview on the most important and clinically relevant publications. Recently, there has been evidence for a progressive loss of intrinsically photosensitive retinal ganglion cells (ipRGC) because of oxidative stress in glaucoma. As ipRGC are responsible for the photic transduction to the circadian system and subsequent melatonin secretion, and melatonin is involved in the pathophysiology of circadian desynchronization, sleep disorder, and depression, an impairment of photo-dependent melatonergic signaling may be a common pathway connecting glaucoma with these comorbidities. This fact, as well as the proven retinal neuroprotective role of melatonin, suggests that melatonergic drugs provide a potentially promising treatment strategy supplementing the management of intraocular pressure by pharmacological and surgical measures. Additionally, multidisciplinary treatment focusing on depression and normalization of circadian rhythms might be beneficial for glaucoma patients. Furthermore, glaucoma might be a useful model for studying the pathophysiological interactions between the melatonergic, circadian, and mood systems.


Background

  1. Top of page
  2. Abstract
  3. Background
  4. Method
  5. Melatonin regulation of the circadian system
  6. Circadian misalignment in ophthalmic diseases
  7. Retinal ganglion cell degeneration in glaucoma
  8. Involvement of melatonin in the pathophysiology of glaucoma
  9. The role of melatonin in depression
  10. Summary and clinical implications
  11. Conclusion
  12. References

Glaucoma is a frequent, pathophysiologically heterogeneous ophthalmologic condition characterized by a typical visual field loss pattern from peripheral to central. As a chronic progressive optic neuropathy, it can lead to severe disability and blindness. Currently, the management of glaucoma is focused on controlling the intraocular pressure (IOP) by pharmacological and surgical measures to avoid these consequences.

Glaucoma has also been reported to be associated with a dysregulation of the circadian system [1], as well as a high incidence of sleep disorders [2, 3], depression, and anxiety [4]. However, because of the higher incidence of all these conditions in older age, they have not received much clinical or scientific attention and remain often undertreated. Recently, there has been evidence that glaucoma leads to an impairment of the photo-dependent melatonin production with alterations in circadian rhythms. Taking into account the possible pathophysiological connection this mechanism has to sleep disorders and depression, this may indicate a common pathway connecting glaucoma with these comorbidities.

In the current review, we will present the state of knowledge on the impact of glaucoma on the melatonergic system and possible links to circadian desynchronization, sleep disorders, and depression. The implications indicating that glaucoma may also be a psychochronobiological disease and their consequences for research and clinical therapy are discussed.

Method

  1. Top of page
  2. Abstract
  3. Background
  4. Method
  5. Melatonin regulation of the circadian system
  6. Circadian misalignment in ophthalmic diseases
  7. Retinal ganglion cell degeneration in glaucoma
  8. Involvement of melatonin in the pathophysiology of glaucoma
  9. The role of melatonin in depression
  10. Summary and clinical implications
  11. Conclusion
  12. References

Medline searches were performed using ‘glaucoma’, ‘melatonin’, ‘circadian rhythm’, ‘sleep disorder’, and ‘depression’ as search terms. Available literature from 1970 onwards was screened for relevance, and additional material was added from the bibliography of applicable papers.

The current review discusses potential pathophysiological mechanisms, a topic that cannot yet be approached via systematic reviews. Therefore, the literature is presented as a narrative review, providing an overview on the most important and clinically relevant publications concerning the role of melatonin in glaucoma and its comorbidities.

Melatonin regulation of the circadian system

  1. Top of page
  2. Abstract
  3. Background
  4. Method
  5. Melatonin regulation of the circadian system
  6. Circadian misalignment in ophthalmic diseases
  7. Retinal ganglion cell degeneration in glaucoma
  8. Involvement of melatonin in the pathophysiology of glaucoma
  9. The role of melatonin in depression
  10. Summary and clinical implications
  11. Conclusion
  12. References

The suprachiasmatic nucleus (SCN) is the primary circadian pacemaker of the human brain and light the most important synchronizer of the circadian system [5]. The circadian system is the major coordinator of sleep and wake phases, but also of many other physiological functions. A circadian misalignment of the human nyctohemeral rhythm, also referred to as chronodisruption [6], can therefore lead to a wide range of biologic consequences in the organism [7–9], including elevated cancer risk [10, 11].

Melatonin as a modulator of the electrical activity in SCN neurons, acting primarily via MT1/MT2 receptors [12] and GABAergic mechanisms [13–15], is therefore recognized as the most important natural substance modulating sleep and circadian rhythm. The time course of melatonin secretion from the pineal gland is adapted to the circadian rhythm and controlled by the SCN and sympathetic fibers originating from the superior cervical ganglia [16].

Light intensity and certain critical wave lengths (460–480 nm) seem to influence melatonin secretion via a specific pathway [17, 18]. The photic input from the eyes is transmitted through the retinohypothalamic tract to the SCN [19] and from there to the upper part of the thoracic spinal cord, the superior cervical ganglia, and the pineal gland [20]. The standard retinal pathways from the retinal rod and cone cells are not involved in this photoentrainment [21]. The SCN receives photic input from other specialized signal transduction mechanisms of intrinsically photosensitive cells in the retina [22], the so-called intrinsically photosensitive retinal ganglion cells (ipRGC). These cells have been shown to be sensitive to light wavelengths different from the classical visual system, and they react slowly and tonically to luminance changes [22, 23]. ipRGC photoreceptors contain the pigment melanopsin, a new opsin playing a major role not in the image formation, but in the nonvisual phototransduction to the SCN and thereby synchronizing circadian rhythms [24–27].

Circadian misalignment in ophthalmic diseases

  1. Top of page
  2. Abstract
  3. Background
  4. Method
  5. Melatonin regulation of the circadian system
  6. Circadian misalignment in ophthalmic diseases
  7. Retinal ganglion cell degeneration in glaucoma
  8. Involvement of melatonin in the pathophysiology of glaucoma
  9. The role of melatonin in depression
  10. Summary and clinical implications
  11. Conclusion
  12. References

Both external and internal factors may lead to an inadequate exposure to the light–dark cycle and subsequently to a gradual shift or a total desynchronization of the circadian system. A reduced photic input can occur because of inadequate light exposure as a result of an individual’s life conditions (e.g., in shift workers), but can also be physiological, for example in older persons. In old age, the circadian phase responsiveness is considered reduced and brighter light seems to be needed to achieve normal amplitudes of the activity rhythms [28–30]. Thus, the average amount of illumination is probably insufficient to adjust the circadian system [31].

Besides old age, various ophthalmic diseases are the most important causes affecting the photic input via a reduced light transmission (e.g., cataract, diabetic retinopathy, macular degeneration, retinitis pigmentosa, optic nerve atrophy, and glaucoma). The literature suggests that among blind individuals a high incidence of sleep disorders is found [32], probably caused by a circadian misalignment and disarranged or even free-running circadian and melatonin rhythms [33–35]. Such sleep disorders, caused by circadian misalignment, are known as advanced/delayed sleep phase syndromes, usually including difficulties sleeping at night, and being sleepy during the day [36].

Vision loss, however, does not necessarily cause a disturbed light transmission to the SCN, which is only regulated by the ipRGC. This hypothesis is supported by clinical studies suggesting that bright light therapy can improve sleep disorders in blind patients with an intact circadian rhythm response to light [37, 38], as well as by patients without visual impairment that show circadian dysfunction with diminished reaction to photic stimulation [39]. The major ophthalmological disease that induces degeneration of ipRGC is glaucoma.

Retinal ganglion cell degeneration in glaucoma

  1. Top of page
  2. Abstract
  3. Background
  4. Method
  5. Melatonin regulation of the circadian system
  6. Circadian misalignment in ophthalmic diseases
  7. Retinal ganglion cell degeneration in glaucoma
  8. Involvement of melatonin in the pathophysiology of glaucoma
  9. The role of melatonin in depression
  10. Summary and clinical implications
  11. Conclusion
  12. References

Glaucoma, as a chronic progressive optic neuropathy, is one of the most common causes of blindness in the industrialized countries. IOP, as well as perfusion pressure, systemic hypertension, diabetes, family history, and race, is significant risk factors for the development of the disease [40].

There is recent evidence that glaucoma should be recognized as a neuropathy that involves the loss of ipRGC, thereby altering the retinohypothalamic tract regardless of the exact IOP levels [41, 42]. Retinal oxidative stress has been put forth as a common pathway promoting glaucomatous alterations and neurodegeneration [43]. Elevated levels of glutamate, a major excitatory neurotransmitter, cause increased intracellular calcium levels, free radical production, nitric oxide synthesis, and mitochondrial dysregulation, all of which seem to be responsible for oxidative neuronal damage and ipRGC death [44–46]. As ipRGC contain melanopsin that is responsible for the light transduction in ganglion cells and changes in SCN function, ipRGC death leads to a compromised circadian rhythm and optic neuropathy [47, 48].

Data suggest that glaucoma patients may lose a very large percentage of their ipRGC [49]. Because of this continuous and large-scale retinal ganglion cell degeneration, recent literature emphasizes that glaucoma may be the main ophthalmologic disease affecting the photic input to the circadian system [1].

Involvement of melatonin in the pathophysiology of glaucoma

  1. Top of page
  2. Abstract
  3. Background
  4. Method
  5. Melatonin regulation of the circadian system
  6. Circadian misalignment in ophthalmic diseases
  7. Retinal ganglion cell degeneration in glaucoma
  8. Involvement of melatonin in the pathophysiology of glaucoma
  9. The role of melatonin in depression
  10. Summary and clinical implications
  11. Conclusion
  12. References

Beside the important role in the regulation of sleep and the circadian system [5, 16, 50], there are also other important effects of melatonin in the organism. Among its features is the neuroprotective role of melatonin. Melatonin and also its metabolites [51, 52] are potent protectors against oxidative stress in neurons [53] and have been considered candidate substances for the treatment of neurodegenerative diseases of the central nervous system [54–57]. Melatonin is also an effective antioxidant in the retina, acting as a scavenger of light-induced free radicals and inhibiting the nitridergic pathway [58–61] having a protective effect on the photoreceptor’s outer membranes and reversing the effect of ocular hypertension on retinal function [62]. Indeed, in an experimental animal model, the concentration of melatonin in the retina of glaucomatous rats with high IOP was significantly reduced [43]. Interestingly, not only melatonin, but also agomelatine, the novel MT1/MT2 receptor agonist antidepressant, has shown significant neuroprotective features [63].

Melatonin not only protects ocular tissue against free radicals, but also it has a direct effect on the IOP. Several studies have shown circadian changes of the IOP [64] and in particular an effective reduction in the IOP via melatonin [65], mediated principally by the MT3 receptor [66, 67]. In this context, the circadian (physiological reduction during the night) and seasonal rhythmicity of IOP [68, 69] as well as the influences of nocturnal ocular blood flow [70] and sleep [71] on the IOP could be phenomena associated with the timing of melatonin release [72, 73].

Melatonin interacts also with risk factors for glaucoma including systemic hypertension and diabetes, that are known to be associated with the occurrence of glaucoma [74, 75] and elevated IOP [76]. A decrease in melatonin may be involved in the manifestation of stress-induced hypertension [77], while the daily nighttime administration of melatonin has been shown to reduce blood pressure [78, 79]. Furthermore, diabetes influences the circadian secretion and plasma concentration of melatonin [80, 81], so that a global disarrangement of these factors in glaucoma can be hypothesized.

The role of melatonin in depression

  1. Top of page
  2. Abstract
  3. Background
  4. Method
  5. Melatonin regulation of the circadian system
  6. Circadian misalignment in ophthalmic diseases
  7. Retinal ganglion cell degeneration in glaucoma
  8. Involvement of melatonin in the pathophysiology of glaucoma
  9. The role of melatonin in depression
  10. Summary and clinical implications
  11. Conclusion
  12. References

A major role of melatonin in the pathogenesis of seasonal affective disorder (SAD) has long been postulated. Chronodisruption is common in patients with SAD, and bright light therapy is effective in treating this condition via a circadian phase shift [82, 83].

In addition, melatonin and circadian system disturbances have been associated with the pathogenesis of major depressive disorder (MDD), where the nocturnal disruption of melatonin secretion prompted the hypothesis of MDD as a ‘low melatonin syndrome’ [84–86]. Although many studies have confirmed a lowered nocturnal melatonin secretion in depressive patients [86–88], these results are not undisputed, as other studies have reported an increase [89, 90] or even a phase shift of melatonin secretion [91].

Hypercortisolemia and a pathologic dexamethasone-suppression test are common findings in depressive individuals [92, 93], and the dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis in depression has proven to be one of the most important psychoendocrinological findings of recent decades [94, 95]. Melatonin may also play an important part in this context: There is evidence for melatonin receptors in the adrenal gland, and melatonin reportedly inhibits ACTH-stimulated cortisol production [96]. Furthermore, CRH may inhibit the pineal secretion of melatonin, indicating a further possible link between melatonin, HPA axis pathophysiology and depression [85].

Regarding comorbid depression in glaucoma patients, a small number of studies are available, which suffer from methodological problems and inconsistent results. While, for example, Mabuchi et al. [4] found a higher prevalence of depression and anxiety among glaucoma patients, Wilson et al. [97] reported no significant differences in comparison with controls. Nevertheless, studies among patients with visual impairment have repeatedly shown a higher prevalence of depression [98, 99], indicating that it may be a major cause of disability among those patients [100]. These findings could not be completely explained by other factors such as age distribution, degree of visual impairment [97], and use of β-blockers [4, 97].

Summary and clinical implications

  1. Top of page
  2. Abstract
  3. Background
  4. Method
  5. Melatonin regulation of the circadian system
  6. Circadian misalignment in ophthalmic diseases
  7. Retinal ganglion cell degeneration in glaucoma
  8. Involvement of melatonin in the pathophysiology of glaucoma
  9. The role of melatonin in depression
  10. Summary and clinical implications
  11. Conclusion
  12. References

The reviewed literature suggests associations among melatonin, circadian rhythm dysfunction, and depression in the pathophysiology of glaucoma (Fig. 1). The relationship between glaucoma and melatonin in particular seems to be bidirectional, as (i) glaucoma (particularly the death of ipRGC) can affect the rhythm of pineal melatonin production, which in turn, can affect the circadian system activity, and (ii) retinal melatonin could be involved in the pathogenesis of glaucoma.

image

Figure 1.  Presumed relationships among risk factors, pathophysiological changes in glaucoma, ipRGC damage, melatonin, circadian rhythm/sleep disorders, depression, and anxiety. Arrows: positive effects; dotted lines: negative effects. HPA axis, hypothalamic–pituitary–adrenal axis; MDD, major depressive disorder; ipRGC, intrinsically photosensitive retinal ganglion cells; SAD, seasonal affective disorder; SCN, suprachiasmatic nucleus.

Download figure to PowerPoint

Pharmacologically, there is already an indication for melatonergic treatment in MDD, SAD, and sleep disorders. As we have pointed out, current data implies that glaucoma patients, too, could benefit from melatonergic treatment on multiple levels: (i) There are direct positive effects of melatonin on the core etiopathology of glaucoma: Melatonin has been proven to directly reduce IOP significantly through the putative MT3 receptor [66] and, thus, may have clinical potential for treating elevated IOP. Furthermore, the antioxidant potency of melatonin in ocular tissue and the neuroprotective role of melatonin in glaucoma could be of use in the management of the disease [62, 101]. (ii) Indirect positive effects can be achieved by a melatonin-dependent positive influence on systemic blood pressure during the night [78, 79]. (iii) Melatonin treatment can positively influence comorbid circadian misalignment and sleep disorders. Continuous retinal ganglion cell degeneration in glaucoma supports the hypothesis of this condition being the main ophthalmologic disease affecting the photic input to the circadian system and thereby circadian rhythms. Taking into account that glaucoma is more common in older age individuals [102] and that, in older patients, the ability of the pineal gland to produce melatonin is already decreased and the day–night amplitude in melatonin secretion is physiologically lowered [103], we can assume that melatonin treatment may be of advantage for a high number of glaucoma patients. Melatonin and its agonists have already been shown to be effective in the treatment of sleep disorders [50, 104] and to restore the disordered circadian rhythm of blind patients [18, 105]. (iv) Melatonin treatment positively influences comorbid depression. Visually impaired individuals repeatedly show a higher prevalence of depression, and some studies suggest a higher prevalence of depression and anxiety in glaucoma patients. Orally administered melatonin may significantly reduce anxiety scores [106], although these results were not consistent in all studies [107]. With respect to depression, agomelatine, a novel melatonergic antidepressant may also have anxiolytic potency and positively affect sleep disorders [108] by resetting the disturbed sleep/wake cycle [109]. Furthermore, it has exhibited neuroprotective activity [63]. Also taking into consideration the well-known side effects of the older tricyclic antidepressants [110, 111], but also of newer selective serotonin reuptake inhibitors (SSRI) [112] especially on IOP and in older aged patients, agomelatine could possibly gain an important position as antidepressant in glaucoma patients.

The interconnections between melatonin and glaucoma, risk and protective factors, circadian rhythms, depression, and anxiety are numerous. Although it is in part speculation at this point, further studies on the factors promoting and protecting against the development of comorbid depression in glaucoma could possibly provide insight into the interdependence of circadian rhythms and mood disorders and shed light on the pathophysiology of depression [113]. Thus, glaucoma may be a useful model to study the physiological connections between the melatonergic, circadian, and mood regulating systems.

Conclusion

  1. Top of page
  2. Abstract
  3. Background
  4. Method
  5. Melatonin regulation of the circadian system
  6. Circadian misalignment in ophthalmic diseases
  7. Retinal ganglion cell degeneration in glaucoma
  8. Involvement of melatonin in the pathophysiology of glaucoma
  9. The role of melatonin in depression
  10. Summary and clinical implications
  11. Conclusion
  12. References

Currently, the principal treatment for glaucoma consists of the management of IOP. Alternative treatment approaches addressing systemic risk factors, other pathological pathways and comorbidities play a secondary role, especially in the context of routine treatment. Considering the higher prevalence of sleep disorders and depression among glaucoma patients, there is evidence for an additional psychochronobiological treatment approach in standard ophthalmological care.

A positive influence of melatonin in terms of the onset and progression of glaucoma as well as the management of IOP appears plausible: There are multiple nonmutually exclusive lines of evidence that melatonin could be useful in the treatment of glaucoma, i.e., through direct and indirect IOP reduction, providing neuroprotective actions, but also acting systematically and correcting chronodisruption as well as ameliorating psychiatric comorbidities found among glaucoma patients.

Finally, because of the numerous interconnections between glaucoma pathophysiology, melatonin, circadian rhythms, depression, and anxiety, glaucoma research might provide new insights regarding the interdependence of the melatonergic, circadian, and mood systems.

References

  1. Top of page
  2. Abstract
  3. Background
  4. Method
  5. Melatonin regulation of the circadian system
  6. Circadian misalignment in ophthalmic diseases
  7. Retinal ganglion cell degeneration in glaucoma
  8. Involvement of melatonin in the pathophysiology of glaucoma
  9. The role of melatonin in depression
  10. Summary and clinical implications
  11. Conclusion
  12. References