FormalPara Key Summary Points

In this case series, three patients treated with sertraline presented with reduced visual acuity. All patients had been treated with sertraline and developed a maculopathy after use.

These cases suggest the possibility of a rare association between sertraline use and a presumed sertraline-associated maculopathy.

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Introduction

Selective serotonin reuptake inhibitors (SSRIs) are a drug class commonly used in the management of a wide range of psychiatric illnesses including major depressive disorder and generalised anxiety disorder [1]. Sertraline is one of the most commonly prescribed SSRIs, and was dispensed over 11 million times in the United Kingdom in 2016 alone [2]. Known common adverse effects of sertraline include gastrointestinal upset, insomnia, fatigue and headache [3].

Despite the widespread use of sertraline, few ocular side-effects have been documented, with some cases of optic neuropathy and acute angle-closure glaucoma reported [4, 5]. Additionally, five isolated, published cases of presumed sertraline-associated maculopathy have been described [6,7,8,9,10]. In this case series, we describe three further cases of presumed sertraline-induced maculopathy, to add to the growing body of evidence to support this rare association. Patient consent is on file.

Written informed consent for publication was obtained in two out of three cases. In the third case, the patient is not identifiable from the available information and has been included due to the rarity of this disease presentation.

Case Presentation

Case 1

A 36-year-old White woman presented with symptomatic central vision loss, followed by headaches. Initial visual acuity (VA) was 20/110 in the right eye (OD) and 20/100 in the left eye (OS) (correcting with refraction to 20/85 OD and 20/80 OS). On examination, the anterior and posterior segments were unremarkable, with no signs of intraocular inflammation, and normal intraocular pressures. The patient underwent magnetic resonance imaging (MRI) of the brain, lumbar puncture, cerebrospinal fluid (CSF) analysis and retinal nerve fibre layer (RNFL) analysis, all of which were unremarkable. RNFL analysis was performed using the Heidelberg Retina Tomograph (Heidelberg Engineering, Heidelberg, Germany). Stereopsis was normal. Visually evoked response was within normal limits. Optical coherence tomography (OCT) imaging demonstrated disruption of the outer retinal layers and retinal pigment epithelium (RPE) at the foveal centre (Fig. 1). OCT images were obtained using a Heidelberg Spectralis instrument.

Fig. 1
figure 1

Case 1 OCT scans of right and left eyes, respectively, taken on presentation, demonstrating symmetrical bilateral RPE and outer retinal disruption

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The patient had a background of anxiety, depression, mood swings and hypertension. Her depression had been managed with sertraline 50 mg once daily for over 5 years prior to onset of visual symptoms. At the time of presentation she was on no other medication of note in this context. She was advised to discontinue her sertraline, and at 6 months review was showing some architectural improvement on her OCT scan but no subjective or objective improvement in her visual acuity which was measured as 20/110 bilaterally.

Case 2

A 27-year-old White woman presented with a 2-week history of bilateral, central visual disturbance. These symptoms had started 4 weeks after commencing sertraline 50 mg once daily; the patient developed difficulty focusing and light sensitivity. BCVA was 20/100 bilaterally and Humphrey visual field testing (using the Humphrey Visual Field Analyzer 24-2 SITA Standard) demonstrated two central scotomas just above the fixation point, on either side of the vertical midline. Anterior segment examination was unremarkable, with no signs of intraocular inflammation, no vitreous activity and normal intraocular pressures. OCT imaging (Fig. 2) showed symmetrical disruption of the photoreceptor layer directly at the foveal centre.

Fig. 2
figure 2

Case 2 OCT OD and OS shown on the top row, respectively, at presentation, demonstrating bilateral RPE and outer retinal disruption on presentation. OCT OD and OS shown on the bottom row, respectively, 12 weeks after cessation of sertraline, with resolution of RPE/retinal changes

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The patient was already on treatment for panic attacks with propranolol 20 mg once daily for 12 years prior to presentation; otherwise past medical history was unremarkable. She had a 15-units-per-week alcohol history but denied smoking or recreational drug use. The patient immediately ceased sertraline treatment. At 4-week follow-up, VA had improved to 20/25 bilaterally and ocular examination was entirely unremarkable, with healthy optic discs, maculae and peripheral retina. Previous foveal abnormalities noted on OCT had resolved (Fig. 2), with no evidence of disc swelling or nerve fibre layer loss.

Case 3

A 68-year-old White woman presented with bilateral blurred vision and a VA of 20/30 OD and 20/40 OS. Dilated fundus examination revealed pre-existing mild non-proliferative diabetic retinopathy. There were new bilateral central macular changes with OCT imaging (Fig. 3) demonstrating bilateral subfoveal disruption affecting the outer retinal layers and retinal pigment epithelium (RPE), worse on the left. Anterior segment examination was unremarkable and intraocular pressures were normal. OCT angiography showed no notable abnormality of retinal vasculature and traditional and blue-wave autofluorescence imaging. This was conducted using the Spectralis platform (Heidelberg Engineering, Heidelberg, Germany) and did not support alternative diagnoses such as macular telangiectasia type 2.

Fig. 3
figure 3

SD-OCT imaging in cross-sectional and en face orientation. The top half shows imaging from initial presentation; note the lobulated “three-leaf clover” appearance of the maculopathy en face SD-OCT imaging. Imaging shown in the bottom half 14 months post-sertraline cessation shows improvement in the outer retinal/RPE layers bilaterally with some residual maculopathy

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The patient had previously taken other SSRIs including fluoxetine and citalopram over a 7-year period, with no visual symptoms. Sertraline had been initiated for depression 20 months before presentation. Other medical history included well-controlled diabetes type II, hypertension, hypothyroidism, osteoarthritis and gastric bypass surgery. Other regular medications included metformin, losartan, levothyroxine, lansoprazole and aspirin.

VA further declined to 20/30 OD and 20/80 OS before sertraline cessation. Nine months after sertraline cessation, VA improved to 20/25 OD and 20/30 OS, and follow-up OCT (Fig. 3) demonstrated resolution of subfoveal disruption in the left eye and improvement of the disruption in the right eye.

Discussion

To date the ocular side-effect profile of sertraline has been limited, with most published reports describing intraocular pressure changes and optic neuropathy [11]. In this series, we highlight three cases of presumed sertraline-induced maculopathy, to add to the five existing published case reports at the time of writing. In our cohort we noted a wide range of sertraline exposure time before developing symptoms, ranging from 4 weeks to over 5 years. Similarly, after sertraline cessation there was variation in final BCVA and degree of maculopathy resolution, perhaps relating to duration of sertraline exposure.

In our cohort, it appeared that shorter sertraline exposure times resulted in the best reversal of symptoms. The shortest exposure time of 4 weeks resulted in rapid resolution of VA and OCT-scan subfoveal abnormalities on sertraline cessation. The longer 20-month exposure time led to satisfactory improvement in VA from 20/80 OS to 20/30 OS, however with residual OCT abnormalities. The exposure time of 5 years resulted in no visual acuity improvement despite architectural improvement on OCT scan. This appears to be in keeping with Agarwal et al.’s case of presumed sertraline-associated maculopathy following 7 months of sertraline exposure, in which VA improved after 3 months cessation from 20/60 OD and 20/40 OS, to 20/30 bilaterally. Mason et al. and Sener et al. described longer exposure periods of 1 year and over 1 year, respectively, and found no BCVA improvement after treatment cessation.

Anatomical changes found on OCT in our cases were consistent with each other, demonstrating RPE and outer retinal layer disruption. None of the patients gave a history of similar causes of such problems, such as exposure to amyl nitrate or history of solar/laser trauma [12]. Cases in the literature have more variance, though always involving the RPE. Sener et al., Mason et al. and Ewe et al. all noted RPE atrophy, with the latter two specifically noting bull’s-eye maculopathy patterns, resembling chloroquine toxicity. Godara et al. noted macular pigment irregularity with small drusen, inner-outer segment layer disruption and thinning of the outer nuclear layer. Agarwal et al. was the only case to find significant cystic changes with elevation of the RPE.

There are several postulated mechanisms for sertraline-associated maculopathy. Ewe et al. hypothesised that the increased bioavailability of serotonin increases activation of phospholipase C via the 5HT2A receptor [13]. This may lead to increased production of intracellular reactive oxygen species and, finally, retinal degeneration. Agarwal et al. suggested that increased levels of serotonin in the central and peripheral nervous system may interact adversely with RPE and photoreceptor serotonin receptors, via a secondary messenger system consisting of cyclic adenosine monophosphate (cAMP) [14]. This may promote ganglion cell apoptosis and maculopathy development [15]. Ultimately, more research is needed on the serotonin receptor profile and activity of the RPE before a satisfactory pathogenic mechanism can be established. Given the low prevalence of macular toxicity associated with sertraline use, there may need to be another predisposing factor required for disease to manifest.

At present, we must be cautious in presuming that all maculopathy cases reported in the literature were definitely caused by sertraline. However, with increasing reports demonstrating a temporal sequence of events and potential improvement on treatment cessation, as well as a deepening understanding of the biological mechanisms, it is becoming increasingly biologically plausible. Clinicians should be aware of this rare, yet potentially reversible sight-threatening complication of sertraline use.