To better understand this observed link between CAIs and glaucoma patient mood changes, Felipe Medeiros – Professor of Ophthalmology and Vice-Chair of Research at the Bascom Palmer Eye Institute Bascom Palmer Eye Institute, Florida, USA – and colleagues Abdelrahman M. Elhusseiny and Ahmad F. Alzein evaluated patient data from the TriNetX United States Collaborative network, providing their findings in a recently published Ophthalmology Science study.
Here, Medeiros discusses what the study revealed.
Given CAIs are locally acting, what prompted you to examine the potential association between these medications and depression/anxiety?
I saw a patient with long-standing glaucoma who had been treated by an outside physician since 2016. She had initially been prescribed Lumigan, and more recently the doctor added dorzolamide. She claimed that shortly thereafter, she developed marked depressive symptoms, including profound fatigue, low mood, and a loss of motivation to engage in daily activities. Importantly, she did not attribute these symptoms to her glaucoma diagnosis, which she had lived with for many years.
Given the well-described association between systemic carbonic anhydrase inhibitors and mood-related side effects, I considered the possibility that topical dorzolamide, despite being locally administered, could be contributing to her symptoms through systemic absorption. We elected to discontinue dorzolamide, and when the patient returned four weeks later, she reported a striking improvement, describing that she had “regained her life.” This clinical experience prompted us to formally investigate this potential association using large-scale datasets, leading to the study we recently published.
How did you work towards distinguishing the mental health effects of the disease from that of the medication?
This is an important point. We and others have shown that glaucoma, particularly progressive glaucoma, is associated with higher rates of depression and anxiety (1, 2). However, in this case the patient had been diagnosed many years earlier and did not report depressive symptoms at the time of diagnosis. On further evaluation, her outside diagnosis of glaucoma was questionable, as there were no clear signs of optic nerve damage. I therefore discontinued Lumigan as well, and have been following her as a glaucoma suspect. The lack of clear glaucomatous damage, and the temporal relationship between symptom onset and topical CAI initiation, supported a medication-related effect rather than an effect of the disease itself.
Were there any specific study findings that surprised you?
Yes, most notably, the magnitude and consistency of the association were stronger than anticipated for a topically administered medication. Even after rigorous propensity score matching and adjustment for ocular and systemic comorbidities, topical CAI use was associated with a 25–35% higher hazard of depression and a substantially higher likelihood of antidepressant initiation, nearly twofold in the early months after treatment initiation. We were also struck by how early these differences emerged, with significant increases evident as early as three months.
How might ophthalmologists interpret these findings when looking at prescribing CAIs for glaucoma?
These findings should not discourage the use of topical CAIs when they are clinically indicated, but they do suggest that ophthalmologists should be more attentive to neuropsychiatric symptoms after initiating these medications. Routine formal screening for depression or anxiety in busy ophthalmology clinics can be challenging with existing tools, which are often time-consuming and not well integrated into clinical workflows. Our results support a heightened level of clinical awareness, particularly during the first months after starting a topical CAI, and a low threshold for asking patients about mood, energy level, and anxiety symptoms.
Importantly, this study aligns with our prior work demonstrating the feasibility of automated, EHR-based AI tools to identify psychiatric distress in ophthalmology settings without adding burden to clinicians or patients (3). Such approaches may offer a solution for identifying at-risk patients and prompting appropriate follow-up, especially as we move toward more integrated, data-driven models of eye care.
Are there particular patient cohorts that would require clinicians to be especially vigilant with CAIs?
Clinicians should be particularly vigilant when prescribing topical CAIs to patients with a prior history of depression or anxiety, those on psychotropic medications, older adults, and patients with multiple systemic comorbidities or polypharmacy. Increased vigilance may also be warranted during the first few months after initiation, when the risk signal appeared strongest in our study.
How do you hope this work might influence future conversations around glaucoma?
We hope this work broadens the clinical conversation around glaucoma beyond IOP alone and highlights the importance of considering patient-centered outcomes, including mental health. From a research perspective, it encourages further study into systemic and neuropsychiatric effects of commonly used topical therapies. Clinically, it may prompt a more open dialogue between ophthalmologists and patients, and stimulate a more integrated multidisciplinary approach to glaucoma care that accounts for both visual and overall well-being.
References
- A Diniz-Filho et al., “Fast Visual Field Progression Is Associated with Depressive Symptoms in Patients with Glaucoma,” Ophthalmology, 123, 754 (2016). PMID: 26920097.
- S Berchuck et al., “Impact of anxiety and depression on progression to glaucoma among glaucoma suspects,” Br J Ophthalmol, 105, 1244 (2021). PMID: 32862132.
- S Berchuck et al., “A Framework for Automating Psychiatric Distress Screening in Ophthalmology Clinics Using an EHR-Derived AI Algorithm,” Transl Vis Sci Technol, 11, 6 (2022). PMID: 36180026.
