A recent study published in the American Journal of Ophthalmology investigated the association between antidepressant use and the risk of developing nonexudative and exudative age-related macular degeneration (AMD)—as well as the rate of conversion from nonexudative to exudative in patients using specific antidepressants.
Give me some background.
Previous research indicated that retinal nerve fiber layer (RNFL) thickness and central foveal thickness (CFT) were significantly reduced in participants with < 1 year of selective serotonin reuptake inhibitor (SSRI) therapy compared to controls.
- Meaning: SSRIs may influence the cellular health of the retina and choroid, specifically via the serotonergic and anticholinergic pathways.
However: Longer SSRI use showed no significant difference to the control group—suggesting there may be a time- or dose-dependent relationship—with longer-term use potentially causing adaptations.
Go on …
As such: “It is possible that the SSRIs and potentially translating this to the similar antidepressants serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) may have a more beneficial or protective effect on these pathways, particularly in early use of the drug,” the study authors explained.
Now talk about the study.
In this retrospective clinical cohort study, investigators identified patients aged ≥ 40 years from the TriNetX database who used antidepressants.
- This timeframe: October 2004 to October 2023.
These patients were then categorized based on exclusive use of the following antidepressants and compared to a control group without antidepressant use:
- SSRIs
- SNRIs
- TCAs
Note: Patients using multiple antidepressants were excluded from the analysis.
Primary outcomes: The incidence of nonexudative AMD, exudative AMD, and progression from nonexudative to exudative AMD.
Tell me more.
Propensity score matching (PSM) was applied to adjust for 17 confounders, including:
- Age
- Sex
- Smoking status
- Hypertension
- Cardiovascular disease
After PSM, the analysis included:
- 633,535 SSRI users
- 826,404 SNRI users
- 501,873 TCA users
Findings?
Compared to controls, antidepressant use was associated with a significantly reduced risk of:
- Nonexudative AMD
- Risk ratio (RR): 0.606 for SSRIs
- RR: 0.141 for SNRIs
- RR: 0.234 for TCAs
- Exudative AMD
- RR: 0.733 for SSRIs
- RR: 0.161 for SNRIs
- RR: 0.267 for TCAs
- Progression to exudative AMD
- RR: 0.701 for SSRIs
- RR: 0.665 for SNRIs
- RR: 0.676 for TCAs
Let’s dig into potential explanations for these associations.
Previous studies have demonstrated that serotonin 1A (5HT1A) receptor agonists have a neuroprotective effect.
- Consequently: SSRIs can indirectly provide protection of the retina from severe photo-oxidative stress by increasing the amount of serotonin available to bind to receptors.
Further: “SNRIs bind to 5-HT and noradrenaline transporters to inhibit the reuptake of serotonin in a selective manner and, in this way, they are termed as having a ‘dual mode of action,’” the study authors noted.
Finally: Tricyclic antidepressants (TCAs) have also shown beneficial effects in modulating oxidative stress, as demonstrated by the ability of amitriptyline, clomipramine, and imipramine to suppress and decrease the proinflammatory cytokines interleukin-1 beta and tumor necrosis factor alpha.
- Note: Oxidative damage is known to be a cause of inflammation, that if left unaddressed, can lead to AMD.
Limitations?
These included:
- Discrepancies in coding
- Surveillance bias
- Use of retrospective administrative data without imaging
- Absence of standardized diagnostic validation
Take home.
These findings suggest that the use of SSRIs, SNRIs, and TCAs was associated with a lower risk of AMD onset and progression.
Potential mechanisms explaining these associations include:
- Reduced inflammation
- Decreased oxidative stress
- Neuroprotection via upregulation of brain-derived neurotrophic factors and suppression of proinflammatory cytokines
Next steps?
The study authors noted that these results are exploratory and hypothesis-generating, and further prospective and mechanistic studies are required to elucidate the relationship between antidepressant use and AMD pathophysiology.
But take note: The investigators did not support changes in antidepressant prescribing patterns based on this study.