Graylands Hospital Drug Bulletin Ocular Effects of Serotonin Antidepressants North Metropolitan Health Service - Mental Health October 2016 Vol 23 No. 2 ISSN 1323 -1251 Although there is a vast body of literature Summary published about side effects of psychotropic medications and serotonergic medications in SSRIs have been shown to have a higher particular, when it comes to visual prevalence for dry eye than SNRIs. disturbance, the studies seldom describe the visual effects in detail; they only mention TCAs, SSRIs and SNRIs have all been vague terms such as ‘visual disturbances’ or 1 reported to precipitate acute angle-closure ‘visual symptoms’. There is also a tendency for only the more serious effects to be glaucoma reported rather than all levels of visual disturbance. 2 A 2007 paper looking at specific SSRIs and SNRIs may cause mydriasis by side effects causing discontinuation of noradrenergic effects or anticholinergic Selective Serotonin Reuptake Inhibitors effects or by 5-HT 7 effects which can cause (SSRIs) listed ‘visual change’ as the 10 th relaxation of the sphincter muscle of the most likely cause of discontinuation ahead of pupil headaches. 2 Mirtazapine, moclobemide and trazodone Table 1 (at the end of the article) shows the have been reported to cause mydriasis information presented in the Australian Medicines Handbook (AMH) and MIMS TCAs and Antipsychotics have been regarding ocular side effects to be relatively reported to cause accommodation vague and not particularly useful when faced with a clinical situation where your patient is interference by anticholinergic effects complaining of a specific side effect like Reports of SSRI induced EPSEs can, rarely, ‘blurred vision’ and an alternative antidepressant is desired. affect ocular muscles and lead to visual symptoms. To decide which antidepressant is most forgiving regarding visual disturbance, the SSRIs have been linked to optic neuropathy, underlying cause of the visual disturbance possibly via multiple transient vasospasms in should first be considered. Mechanisms of the optic nerve which could progressively medication induced ‘blurred vision’ could be induce ischaemic optic neuropathy. varied including: • Eyelid and keratoconjunctival disorders Dry Eye • Uveal tract disorders • Accommodation interference An association between antidepressant use, • Glaucoma (specifically angle-closure particularly tricyclic antidepressants and glaucoma) . SSRIs, and dry eye, with decreased lacrimal • secretion being the likely mechanism, has Cataract and pigmentary deposits in 3 the lens and cornea been reported in several studies. Animal • Retinal abnormalities/retinopathy studies have suggested several mechanisms: • Dystonia of ocular musculature/oculogyric crisis Graylands Hospital Drug Bulletin April 2016 Vol 23 No.2 Page 1 • Parasympathetic denervation of the muscle of the eye and subsequent human lacrimal gland may cause mydriasis. 9 In patients with a biometric reduced tear flow predisposition to an occludable angle, the • Neuronal release of serotonin (5-HT) further reduction in the width of the may be involved in regulation of iridocorneal angle induced by mydriasis may lacrimal secretions block circulation of the aqueous humour with 9 • Chronic exposure to histamine and 5- the possible development of glaucoma. HT altered the secretory process Stimulation of 5-HT 1A receptors reduces IOP SSRIs have been shown to have a higher and reduces the rate of production of prevalence for dry eye than Serotonin and aqueous humour. This counterbalances the Noradrenaline Reuptake Inhibitors (SNRIs) effect of stimulation of 5-HT 7 which increases 9 despite the SNRIs having more aqueous humour production. Theoretically 3 anticholinergic effects. then, vortioxetine, which is a 5-HT 1A agonist and a 5-HT 7 antagonist, should prove It has been proposed that altered levels of beneficial to raised IOP. serotonin due to SSRI treatment can affect the sensitivity thresholds of corneal nerves, 5-HT 2A/2C receptors are also expressed in the resulting in disruption to tear film which ICB but the effect on IOP has not been fully 4 covers the ocular surface. Serotonin has elucidated. The known effects of 5-HT 2C been detected in human tears, and may stimulation on fluid balance could be a affect corneal nociceptor sensitisation. plausible mechanism for SSRI effects on IOP. Changes in serotonin levels in tears could be The increase in IOP caused by fluoxetine in associated with specific dry eye subtypes.5 rabbits has been inhibited by the selective 5- 9 HT 2A antagonist ketanserin. Other proposed mechanisms for increase Glaucoma pressure include ciliochoroidal effusion or an immune reaction in choroidal tissue. 10 Tricyclic antidepressants (TCAs) and SSRIs However, Murphy et al makes the point that e.g., citalopram, escitalopram, fluoxetine and many drugs with probable Naranjo scores are paroxetine and the SNRI venlafaxine, have involved in serotonin and dopamine been reported to precipitate acute angle- metabolism. 10 Interestingly, although there closure glaucoma. There have also been are case reports of glaucoma associated with case reports of other antidepressants bupropion use, Kimat et al report a significant precipitating acute angle-closure e.g. inverse association with bupropion use and 6 mirtazapine. glaucoma.11 Their explanation is that bupropion may be protective against the The underlying mechanism is pupillary block development of glaucoma through inhibition caused by pupil dilatation, which is attributed 11 of TNF-alpha. to the significant anticholinergic and serotonergic side effects of these Clinicians should consider referring patients 6-8 antidepressants. The role of serotonin in at increased risk of acute angle-closure human ocular physiology has yet to be fully glaucoma for an ophthalmic assessment prior determined, however, serotonin is known to to prescribing SSRIs. 8 be an effector on various smooth muscle including the ciliary muscle and sphincter of the eye. 9 Dysfunction of the serotonin system has been implicated in intra ocular pressure (IOP) modifications. It is believed that serotonin 5-HT 1A , 5-HT 2A/2C and 5-HT 7 receptors are located at the level of the iris- ciliary body (ICB) complex but only 5-HT 7 receptors have been identified at the level of iris musculature. These receptors are responsible for relaxation of the sphincter Graylands Hospital Drug Bulletin April 2016 Vol 23 No.2 Page 2 Table 2 Bazire’s Recommendations for Antidepressants in Patients with Glaucoma 12 Although SSRIs primarily act as antidepressants by inhibition of reuptake of Lower Risk Moderate Higher serotonin in the central nervous system Risk Risk (CNS), they also lead to increases in Agomelatine Duloxetine Tricyclics available serotonin in other areas of the body Bupropion Mirtazapine such as blood and eye. Some SSRIs also MAOIs SSRIs have effects on dopamine, cholinergic and Moclobemide Venlafaxine adrenergic receptors. The serotonin receptors Trazodone thought to be involved in the dynamics of intraocular pressure in the eye are 5-HT 1A , 5- Vortioxetine 1 HT 2A , 5HT 2C and 5-HT 7. Patients with narrow angle glaucoma can be SSRIs may cause mydriasis by noradrenergic prescribed anticholinergic medication effects or anticholinergic effects or by 5-HT 7 effects which can cause relaxation of the provided intraocular pressure is monitored. 1 The main symptoms of narrow angle sphincter muscle of the pupil. glaucoma are blurred vision, coloured halos Mydriasis around bright lights, intense pain, lacrimation, 12 lid oedema, red eye, nausea and vomiting. Dilation of the pupil of the eye, especially when excessive or prolonged, is usually as a result of trauma, a medical disorder or a drug. Uveal Tract Effects Antidepressants that can cause dilation of the The uveal tract is a layer of tissue located pupil include SSRIs, mirtazapine, moclobemide and trazodone. 12 Mydriasis has between the outer layer (cornea and sclera) 12 and the inner layer (the retina) of the eye. been reported with duloxetine. The front portion (anterior) of the uveal tract This effect does not seem to cause major contains the iris, and the back portion visual discomfort or problems, unless it (posterior) of the uveal tract contains the becomes associated with a dramatic increase choroid and the stroma of the ciliary body. in IOP and with eventual glaucoma attacks. The mydriatic effects of SSRIs are likely to be reversible after cessation of therapy, Figure 1. Structure of the eye with the uveal tract labelled red. especially if they do not become complicated The uvea can be divided into three parts: the iris, the ciliary 1 body, and the choroids. 13 by angle-closure glaucoma. Accommodation Interference TCAs and antipsychotics have been reported to cause visual accommodation interference via their anticholinergic effects. 1 No reports of SSRIs or SNRIs having this effect were found. Since some of the SSRIs do have significant anticholinergic effects e.g. fluoxetine, it should be expected that accommodation difficulties could be caused by fluoxetine. Cataract and Pigmentary Deposits in the Lens and Cornea Reviews considering causes of ocular adverse effects are concerned firstly with photosensitivity e.g. chlorpromazine and then Graylands Hospital Drug Bulletin April 2016 Vol 23 No.2 Page 3 the effects of atypical antipsychotics. Antidepressants generally were not mentioned. Other Reported Ocular Side Effects Retinal Abnormalities/Retinopathy SSRIs have been linked to optic neuropathy. 16 The proposed mechanism