calls for eye screening BEFORE taking antidepressants

[Guest guest]

" These considerations suggest the need to include an

ophthalmological examination in the protocol of depressed patients

before starting SSRI administration. ........... "

Br J Ophthalmol 1998;82:976 ( August )

Correspondence

Acute glaucoma, chronic glaucoma, and serotoninergic drugs

Reply

Authors' reply

Acute glaucoma, chronic glaucoma, and serotoninergic drugs

EDITOR,We were interested to read Kirwan et al's report of acute

angle closure glaucoma (AACG) associated with the antidepressant

paroxetine (Seroxat),1 as we have reported a similar case.2 In

Kirwan's report, AACG occurred within 24 hours of the first dose,

suggesting an anticholinergic mechanism. Our case became symptomatic

some 2 weeks after daily dosage was commenced, leading us to

postulate that the effect could have been mediated by serotoninergic

pathways. This raises the possibility of other important ocular side

effects with drugs of this class.

Paroxetine is an antidepressant of the selective serotonin reuptake

inhibitor (SSRI) class. SSRIs act by inducing a gradual rise in

postsynaptic levels of serotonin (5-hydroxytryptamine, 5-HT) via

desensitisation of the feedback systems which control the rate

limiting enzyme in 5-HT synthesis.3 The 5-HT receptors involved have

not yet been fully elucidated, and their role in ocular physiology

is a subject of ongoing research. In animal studies, serotoninergic

stimulation may cause mydriasis, and can have an independent effect

in raising the intraocular pressure (IOP).4 Receptors for 5-HT have

been demonstrated in the human eye.5

It is therefore possible that SSRIs could have an effect on IOP in

humans. Consequently, we should look for raised IOP and open angle

glaucoma as a side effect of SSRIs. A recent study has shown a

significant short term rise in IOP after a single oral dose of the

SSRI fluoxetine (Prozac). Twenty depressed patients were given

either fluoxetine 20 mg or placebo in a randomised crossover blinded

study, and fluoxetine was associated with a mean IOP elevation of

over 4 mm Hg, lasting 6-8 hours.6 We have been unable to find any

publication regarding the effect on IOP in the longer term, but we

have recently become aware of previously unpublished data which

partly address this issue.

In premarketing and subsequent clinical trials of fluoxetine, 585

adult patients of a wide age range have been assessed.

Ophthalmological examinations were made at baseline, and again after

a treatment period which ranged between less than 1 month and 24

months. " Five out of the 585 patients had a change in intraocular

pressure... . One had a decrease in IOP which was determined to be

clinically insignificant [29 year old female, dosage 20 mg/day,

examined at 1 month]. Four patients experienced an elevation: in one

patient the elevation was considered a normal diurnal variation [74

year old male, dosage 80 mg/day, examined at 2 months], in a second

patient the elevation was felt to be related to angle closure [59

year old male, dosage 80 mg/day, examined at 1 month], the third

patient acknowledged cocaine use prior to the examination and this

was considered the probable explanation [37 year old male, dosage 80

mg/day, examined at 12 months], and the fourth patient had a l mm Hg

rise with no probable extenuating circumstances [26 year old female,

dosage 80mg/day, examined at 2 months] " (Dista Products Limited,

personal communication).

Voluntary reporting of suspected adverse events with fluoxetine has

identified a total of 63 cases of " glaucoma " in an estimated patient

population of 21 million (Dista Products Limited, personal

communication). The manufacturers of paroxetine are aware of four

cases of AACG, six of " glaucoma (unspecified) " , and one of raised

IOP, in a UK patient population of over one million (Kline

Beecham Pharmaceuticals, personal communication).

These data indicate that our understanding of the effect of SSRIs on

IOP is still unclear. The demonstration of a short term IOP rise

after a single fluoxetine dose6 implies that chronic dosage could

lead to a sustained elevation of IOP. However, the manufacturer's

own data suggest that this is not the case, in that less than 1% of

patients showed any IOP change after treatment. The low incidence of

reported glaucoma with SSRIs does not exclude a real effect: many

clinicians may not suspect a particular drug to be a contributory

factor when diagnosing a particular condition, especially if a

causal relation has not been suggested in the literature. This is

particularly true of open angle glaucoma, which is common and

usually idiopathic, and of AACG, which is rarer but occurs in

anatomically predisposed eyes.

We feel that this area merits further study and clarification,

particularly regarding the effect of long term SSRI administration

on IOP. In the meantime, we would encourage colleagues to report

cases of glaucoma or raised IOP which may be associated with SSRIs

to the Committee on Safety of Medicines.

TOM EKE

Department of Ophthalmology, Leicester Royal Infirmary, Leicester

LEI 5WW

SUSAN CARR

Drug Information Centre, Leicester Royal Infirmary, Leicester LEI 5WW

References

1. Kirwan JF, Subak-Sharpe I, Teimory M. Bilateral acute angle

closure glaucoma after administration of paroxetine. Br J Ophthalmol

1997;81:252[Free Full Text].

2. Eke T, Carr S, Bates AK. Acute angle closure glaucoma associated

with paroxetine. BMJ 1997;314:1387[Free Full Text].

3. Briley M, Moret C. Neurobiological mechanisms involved in

antidepressant therapies. Clin Neuropharmacol 1993;16:387-400

[Medline].

4. Osborne NN. Serotonin and melatonin in the iris/ciliary

processes and their involvement in intraocular pressure. Acta

Neurobiol Exp 1994;54(Suppl):57-64[Medline].

5. Barnett NL, Osborne NN. The presence of serotonin (5-HT1)

receptors negatively coupled to adenylate cyclase in rabbit and

human iris-ciliary processes. Exp Eye Res 1993;57:209-216[Medline].

6. Costagliola C, Mastropasqua L, Steardo L, et al. Fluoxetine oral

administration increases intraocular pressure. Br J Ophthalmol

1996;80:678[Medline].

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Reply

EDITOR,In 1991 Ahmadl first reported the occurrence of glaucoma,

probably an acute angle closure glaucoma (AACG), in a 35 year old

man as a result of fluoxetine administration, during the fifth week

of therapy. More recently, also Kirwan et al 2 and Eke et al 3

described two cases of AACG associated with the administration of

paroxetine, an antidepressant which acts as a selective inhibitor of

the serotonin neuronal uptake (SSRI). In 1996 we described the

effect of fluoxetine oral administration on intraocular pressure

(IOP) in 20 consecutive depressed patients and demonstrated that

after a single dose of 20 mg IOP was significantly increased.4

Serotonin (5-HT) is present in mammalian iris ciliary body and

cornea at higher concentration than in non-mammalian species.5 While

a transmitter role for serotonin in the retina has been established,

conflicting data exist in the literature on whether or not

activation of serotonin receptors can cause changes in IOP.

Experimental evidences demonstrated that topical application of

serotonin increased IOP in rabbit eyes, and that 5-

carboxamidotryptamine, a 5-HTla receptor agonist, is even more

effective than 5-HT itself in elevating IOP.6 These results confirm

the involvement of serotonin receptors in the regulation of IOP, and

the fact that ketanserin, a compound with serotonergic blocking

properties, reduces IOP in animals and humans emphasises the role

exerted by 5-HT on IOP.7

To date, no long term studies regarding the effect of SSRI on IOP

have been published. We know the prevalence of primary open angle

glaucoma (POAG) (conservatively estimated to be approximately 1/200

of the general population over the age of 40 years)8 and that of

AACG (approximately 1/1000 individuals over the age of 40 years),8

while the incidence of new cases within the population treated with

SSRI has not yet been evaluated, with the exception of the

manufacturer's own data, which do not show a significant occurrence

of IOP changes induced by SSRI treatment (Dista Products Limited,

personal communication; Kline Beecham Pharmaceuticals, personal

communication). POAG is an asymptomatic disease, until significant

visual field loss occurs, and a single IOP reading does not

necessarily exclude or confirm the diagnosis. The rise in IOP after

a single dose of SSRI was about 4 mm Hg4 in a non-glaucomatous

population, equivalent to the diurnal fluctuations of IOP found in

normal subjects,8 and probably is without long term effect on the

ganglion cell integrity. On the contrary, this same variation,

together with the small changes in pupil size reported by other

investigators,6 in the so called " predisposed eyes " (that is,

patients with positive family history of glaucoma and/or patients

with physiological risk factorsrelatively anterior location of the

iris-lens diaphragm, shallow anterior chamber, and narrow entrance

to the chamber angle) is able to modify the hydrodynamic homeostasis

of the eye, leading to the acute angle closure.

These considerations suggest the need to include an ophthalmological

examination in the protocol of depressed patients before starting

SSRI administration.

CIRO COSTAGLIOLA

Eye Clinic, II University of Naples

LEONARDO MASTROPASQUA

Eye Clinic, e D'Annunzio University of Chieti

LUCA STEARDO, NUNZIO TESTA

Department of Neurology, Federico II University of Naples, Via S

Pansini, 5 80131 Napoli, Italy

References

1. Ahmad S. Fluoxetine and glaucoma. Ann Pharmacother 1991;25:436

[Medline].

2. Kirwan JF, Subak-Sharpe I, Teimory M. Bilateral acute angle

closure glaucoma after administration of paroxetine. Br J Ophthalmol

1997;81:252[Free Full Text].

3. Eke T, Carr S, Bates AK. Acute angle closure glaucoma associated

with paroxetine. BMJ 1997;314:1387[Free Full Text].

4. Costagliola C, Mastropasqua L, Steardo L, et al. Fluoxetine oral

administration increases intraocular pressure. Br J Ophthalmol

1996;80:678[Medline].

5. Osborne NN, Tobin AB. Serotonin accumulating cells in the iris-

ciliary body and cornea of various species. Exp Eye Res 1987;44:731-

746[Medline].

6. Osborne NN, Meyer-Bothling U, Barnett NL. Serotonin receptors in

the eye. In: DR, Drance SM, eds. Encounters in glaucoma

research. I: Receptor biology and glaucoma. Milan: Fogliazza

Editore, 1994;331-360.

7. Costagliola C, Iuliano G, Rinaldi M, et al. Effect of topical

ketanserin administration on intraocular pressure. Br J Ophthalmol

1993;77:344-348[Abstract].

8. Kanski JJ, McAllister JA. Glaucoma a colour manual of diagnosis

and treatment. Oxford: Butterworth-Heinemann, 1991;40-57.

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Authors' reply

EDITOR,Eke et al's letter raises several interesting points. The

rapid onset of acute angle closure glaucoma in our case implies an

anticholinergic mechanism. The patient in Eke's report may simply

have had an anticholinergic response to commencement of the higher

dose 3 days before. However, the serotoninergic mode of action with

this agent does raise the issue of both a mydriatic effect and an

effect in eyes with open angles. As with any recently introduced

class of drug, it is important for clinicians to monitor closely

possible adverse effects.

So far the data reported from the manufacturers reveal a minimal

number of cases of raised intraocular pressure, not different from

the probable incidence of primary open angle glaucoma in the general

population. However, a small study with careful monitoring of

intraocular pressure demonstrated a small but significant elevation

of IOP over 12 hours.1 Subjects were, however, young adults and the

study was over a short period. We have little idea what happens over

the longer term. For example, tricyclic antidepressants have

profound anticholinergic side effects on commencement of treatment

to which patients physiologically adapt to the point that sudden

withdrawal leads to a rebound cholinergic syndrome. The effect in

older patients, those with anatomically predisposed narrow angles,

or indeed glaucoma patients may be very different. If this class of

agents does increase intraocular pressure by 4 mm Hg in a sustained

fashion this could potentially have clinical implications in

population terms for glaucoma risk. In the year ending August 1994,

British general practitioners wrote 13 million prescriptions for

antidepressants.2 A significant proportion of these were SSRIs.

Should the possibility of this class of agent causing an elevation

of intraocular pressure modify their current use? In general the

answer should be no. Depression is common; the estimated lifetime

prevalence of " major depression " in women is between 4.9% and 8.7%

and in men, 2.3-4.4% with even higher figures applying to the less

severe end of the spectrum.3 Depression is a severe, disabling

disease. It has a high mortality. It is estimated that severe

depressive illness increases the risk of suicide by a factor of 30

such that 15% die by suicide.4 Alternative treatments with other

antidepressants are generally less well tolerated, especially in the

elderly. Despite the possibility of raised intraocular pressure the

risk/benefit ratio will almost always favour treating depression

with the optimum agent.

Until the real effect of SSRIs on IOP has been ascertained it is

difficult to make suggestions on management and further evidence on

this subject is required. However, it would seem prudent to closely

monitor glaucoma patients who have recently commenced treatment with

an SSRI. Given limited ophthalmic resources, until we know more

about the long term effects of these drugs on IOP it does not seem

reasonable to recommend ophthalmological screening of all patients

commenced on SSRIs.1 Like Eke and Carr, we encourage colleagues to

report cases of glaucoma or raised IOP that may be due to therapy

with SSRIs. Additionally, we would stress the importance of

communication between disciplines so that no doctor is unaware of

prescribed medication.

JAMES F KIRWAN

Department of Ophthalmology, St 's Hospital, Blackshaw Road,

London SW17 0QT

JOHN P STEPHENS

Department of Psychosomatic and Liaison Psychiatry, St 's

Hospital, Blackshaw Road, London SW17 0QT

References

1. Costagliola C, Masttropasqua L, Steardo L, et al. Fluoxetine

oral administration increases intraocular pressure. Br J Ophthalmol

1996;80:678[Medline].

2. Scriptcount 300 MAT to 26/8/94 [program]:

Healthcare.

3. Robins LN, Helzer JE, Weissman MM. Lifetime prevalence of

specific psychiatric disorders in three sites. Arch Gen Psychiatry

1984;41:949-958[Abstract].

4. Guze S, Robins E. Suicide and primary affective disorder. Br J

Psychiatry 1970;117:437-438[Medline].

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© 1998 by British Journal of Ophthalmology