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Antiglaucoma medication and clinical depression

Isaac Schweitzer, Kay Maguire, Virginia Tuckwell

Objective: The aim of this paper is to alert the medical community to the potential risk of
clinical depression following the use of antiglaucoma medication.
Method: The available literature concerning systemic side-effects of topical antiglaucoma
medication and the association of these agents with clinical depression were reviewed. In
addition, two cases are reported of the occurrence of clinical depression following use of
topical betaxolol which only resolved completely after switching glaucoma medication.
Results/Conclusions: The case reports presented here add to the increasing body of
literature linking topical ophthalmic -adrenoceptor antagonists with depression. While these
cases are uncommon, this phenomenon continues to be poorly recognized by the medical
profession, psychiatrists, ophthalmologists and general practitioners alike.
Key words: beta-blockers, betaxolol, depression, topical.

Australian and New Zealand Journal of Psychiatry 2001; 35:569571

Beta-adrenoceptor antagonists (beta-blockers) are reported to the National Registry of Drug-Induced


widely used as both systemic and topical medications. Ocular Side-effects in the USA between 1978 and 1985.
Topical ophthalmic beta-blockers are the treatment of Of these, 20 cases were acute suicidal depression. A
choice in glaucoma and ocular hypertension manage- review by Bourgeois [4] refers to a further 10 published
ment due to their favourable efficacy and acceptable reports linking timolol to depression as well as several
safety and tolerability profiles. They reduce intraocular reports casting doubt over the occurrence of depression
pressure thus preventing damage to the optic nerve and following timolol.
subsequent loss of vision. Timolol, betaxolol and levo- Betaxolol is a more specific 1 adrenoceptor antago-
bunolol are the topical beta-blockers currently available nist than timolol [1]. This specificity and its increased
in Australia. lipophilicity, high plasma protein binding and large
Topical beta-blockers are systemically absorbed in volume of distribution would suggest that betaxolol
small amounts from the nasopharyngeal mucous mem- would have less systemic side-effects than timolol.
branes [1]. This can lead to adverse effects on the car- Double-blind crossover studies have compared central
diovascular and pulmonary systems [1]. nervous system (CNS) symptoms following administra-
Depressive symptoms were reported in 17/165 patients tion of timolol and betaxolol suggesting that betaxolol
after administration of timolol over two decades ago [2]. may cause less depressive symptoms than timolol [1].
Shore et al. [3] reported that depression accounted for Despite this, betaxolol has been associated with clinical
17% of 369 central nervous system reactions to timolol depression. A woman was hospitalized with severe
depression which commenced with the administration
of betaxolol and resolved within 10 days of stopping
it [5]. Bourgeois [4] reports a further two studies with
Isaac Schweitzer, Healthscope Chair of Psychiatry (Correspondence);
K. Maguire, Research Fellow; V. Tuckwell, Research Fellow cases of depression induced by betaxolol and the Aus-
The Melbourne Clinic, Department of Psychiatry, The University tralian Adverse Drug Reaction Advisory Committee
of Melbourne. Address for correspondence: 130 Church Street, have two reports of depression associated with betaxolol.
Richmond, Victoria 3121, Australia.
Email: i.schweitzer@medicine.unimelb.edu.au This paper describes two further cases to alert the medi-
Received 16 November 2000; revised 15 February 2001; accepted cal community to this continuing source of psychiatric
22 February 2001. morbidity.

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570 ANTIGLAUCOMA MEDICATION AND DEPRESSION

Case 1 his treating psychiatrist. He had first experienced depres-


sion in his late 20s and had been treated with anti-
Mr X. was a 65-year-old former bank manager who depressants. He had mostly been well and had worked
worked part-time as a landscape gardener. He was married effectively until retirement 5 years ago. He described a
for the second time, his relationship was satisfactory good marriage but they were not close and led somewhat
and there were no stressors. He had had an episode of independent lives. He had been on lithium prophylaxis
depression 15 years previously and had made a good for many years but this had been considered only partly
recovery with electroconvulsive therapy (ECT). This had helpful in preventing recurrences. He had been treated
been in the context of restructuring in his work situation with tricyclic antidepressants, monoamine oxidase inhib-
and a period of major stress that led to his retirement itors, selective serotonin reuptake inhibitors and ECT in
from banking. the past.
He dated the beginning of this episode of depression His depressive symptoms included a loss of energy,
from the onset of his glaucoma. This was treated with sleep disturbance, obsessional ruminations, social with-
betaxolol 0.5% (1 drop b.d.). His symptoms included drawal, anhedonia, loss of libido, loss of appetite but no
loss of energy, loss of his sense of humour, sleep distur- loss of weight. There was no guilt or psychotic symp-
bance and lack of libido. His general practitioner com- toms. He was treated with venlafaxine and initially made
menced him on fluoxetine but as he failed to respond he a good improvement but he remained symptomatic and
was referred to the author (IS). On admission to hospital, his mood fluctuated. His wife complained that he remained
his symptoms included poor appetite, weight loss of anergic, uncommunicative and listless. Initially his dose
5 kg, feeling useless, agitation and he was visibly slowed of venlafaxine was gradually increased to 375 mg but
down, leading to a diagnosis of major depression with this resulted in agitation without improvement in his
melancholic features. mood. Soon after the good result with case 1, the author
Treatment with an increased dose of fluoxetine failed, (IS) enquired about his glaucoma. He confirmed that
so a course of ECT was commenced. He rapidly improved he was taking betaxolol eye drops (betaxolol 0.5%,
with ECT then plateaued and this was ceased after 15 1 drop b.d.) and had been for the past 3 years. Again after
treatments as he started to develop post-ECT confusion communication with his ophthalmologist and changing
and marked memory problems. He was commenced to latanoprost he also reported a rapid improvement.
on venlafaxine and discharged improved but not fully
recovered. His energy level, work capacity, sense of Discussion
humour and his libido were not as they had been. His
dose of venlafaxine was gradually increased to 375 mg The two case reports described above point to an asso-
with little change. He never felt fully rested, he had to ciation between topical betaxolol and clinical depres-
constantly push himself at work and complained of a sion. Combined with other published data [4,5] and
dull aching fuzziness in his head. previous reports for timolol, it appears that these beta-
He attributed the onset of his depression to the glau- blockers may cause depressive symptoms in some indi-
coma and began to wonder whether the eyedrops were viduals. That betaxolol caused the depressive symptoms
having an adverse effect. Ten months following his dis- cannot be proven conclusively, however, in each case
charge to reassure him the author (IS) made a literature there is a clear temporal association between the com-
search and was surprised to discover reports of depres- mencement of the eye drops and the onset of depressive
sion following timolol eye drops. Subsequently the treat- symptoms and the rapid recovery of mood following ces-
ing ophthalmologist changed his drops to latanoprost. sation of the beta-blocker. In both cases the patients had
Mr X. reported that his mood lifted within 48 h a cloud made a partial recovery with conventional antidepressant
lifted, the fuzzy feeling evaporated, and he began to feel treatment and it was only when the betaxolol eye drops
more energetic. After two weeks, both he and his wife were withdrawn, that full recovery occurred.
agreed that he was back to his normal self. He remained It was first reported in 1967 that oral ingestion of beta-
on venlafaxine for another year and stopped it under blockers may cause depression. Subsequent investiga-
supervision. Three years after admission he remained tions using prospective, case-matched studies have not
well. confirmed this. A recent publication has suggested that
beta-blockers may have been unjustly associated with
Case 2 depression as previous studies had used antidepressant
prescriptions rather than diagnosis of depression in their
A 70-year-old married and retired scientist was analysis. This was found to be a poor marker of depres-
referred for treatment of his recurrent mood disorder by sion by the more recent study [6]. The potential for

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I. SCHWEITZER, K. MAGUIRE, V. TUCKWELL 571

newly prescribed beta-blockers to cause depression was While these cases are uncommon, this phenomenon
not evaluated and thus not ruled out in this study as only continues to be poorly recognized by the medical profes-
on-going beta-blocker use was investigated [6]. sion, psychiatrists, ophthalmologists and general prac-
Theoretically, there are plausible pathophysiological titioners alike. Patients can be educated in techniques to
mechanisms by which beta-blockers could cause depres- limit systemic absorption of topical agents and newer
sion. Down-regulation of 1-adrenoceptors in the CNS formulations such as Beptoptic-S (Alcon Laboratories,
has been associated with the mechanism of action of Frenchs Forest, NSW, Australia) have been designed to
antidepressants, -adrenoceptors are increased in the limit drug exposure. Both will reduce the risk of adverse
brains of suicide victims and in most valid animal model effects, however, potentially dangerous side-effects
of depression [7]. Interestingly, augmentation of antide- warrant careful monitoring by the prescribing physician.
pressant treatment with another beta-blocker pindolol
has recently received much attention. Many studies sug- References
gest that this combination treatment leads to improve-
ment of otherwise refractory patients or a faster onset 1. Rait LL. Systemic effects of topical ophthalmic -adrenoceptor
of antidepressant action. The mechanism of action of antagonists. Australian and New Zealand Journal of
Ophthalmology 1999; 27:5764.
pindolol in this case has been attributed to its affinity for 2. McMahon CD, Shaffer RN, Hoskins HD, Hetherington J.
5-HT receptors as it has been shown by positron emis- Adverse effects experienced by patients taking timolol.
sion tomography (PET) to occupy human 5-HT1A recep- American Journal of Ophthalmology 1979; 88:736738.
tors [8]. Betaxolol however, has negligible affinity for 3. Shore JH, Fraunfelder FT, Meyer SM. Psychiatric side-effects
from topical ocular timolol, a beta-adrenergic blocker. Journal of
5-HT receptors and has different effects to pindolol on Clinical Psychopharmacology 1987; 7:264267.
the actions of fluoxetine [9]. Thus although both drugs 4. Bourgeois JA. Depression and topical ophthalmic beta
are beta-blockers, one has the propensity to induce depres- adrenergic blockade. Journal of the American Optometry
sion whereas the other may help to alleviate it. Association 1991; 62:403406.
5. Orlando RG. Clinical depression associated with betaxolol.
The number of cases involved is small and points to American Journal of Ophthalmology 1986; 102:275.
some patients being more susceptible than others. One 6. Bright RA, Everitt DE. -blockers and depression. Journal of
explanation may lie in the way individual patients metab- the American Medical Association 1992; 267:17831787.
olize particular beta-blockers. Timolol is metabolized by 7. Vetulani J. Current concepts of mechanisms of action of
antidepressant treatments based on preclinical studies.
the cytochrome P450 enzyme CYP2D6. Approximately In: Judd, LL, Saletu, B, Filip, V, eds. Basic and clinical science
310% of the population lack normally active CYP2D6. of mental and addictive disorders (Bibliotheca Psychiatrica 167).
Edeki et al. [10] found that subjects lacking CYP2D6 had Basel: Karger, 1997:162167.
8. Andree B, Thorberg SO, Halldin C, Farde L. Pindolol binding
greater systemic effects and higher plasma concentrations
to 5HT1A receptors in human brain confirmed with positron
of timolol following topical administration of timolol. In emission tomography. Psychopharmacology 1999;
the case of betaxolol, this may also be the explanation. 144:303305.
A minor metabolite of betaxolol, -hydroxylated betax- 9. Gobert A, Millan MJ. Modulation of dialysate levels of
dopamine, noradrenaline, and serotonin (5HT) in the frontal
olol, can be catalysed by CYP2D6. Further evidence for cortex of freely-moving rats by (-) -pindolol alone and in
this explanation comes from the observation that CNS association with 5HT reuptake inhibitors: comparative roles of
complaints were more common in those patients with beta-adrenergic, 5-HT1A, and 5-HT1B receptors.
more profound decreases in intraocular pressure due pos- Neuropsychopharmacology 1994; 21:268284.
10. Edeki TI, He H, Wood AJJ. Pharmacogenetic explanation for
sibly to higher drug concentrations [2]. excessive beta-blockade following timolol eye drops: potential
These case reports add to the literature linking topical for oralophthalmic drug interaction. Journal of the American
ophthalmic -adrenoceptor antagonists with depression. Medical Association 1995; 274:16111613.

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