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

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570 ANTIGLAUCOMA MEDICATION AND DEPRESSION
Case 1
Mr X. was a 65-year-old former bank manager who
worked part-time as a landscape gardener. He was married
for the second time, his relationship was satisfactory
and there were no stressors. He had had an episode of
depression 15 years previously and had made a good
recovery with electroconvulsive therapy (ECT). This had
been in the context of restructuring in his work situation
and a period of major stress that led to his retirement
from banking.
He dated the beginning of this episode of depression
from the onset of his glaucoma. This was treated with
betaxolol 0.5% (1 drop b.d.). His symptoms included
loss of energy, loss of his sense of humour, sleep distur-
bance and lack of libido. His general practitioner com-
menced him on fluoxetine but as he failed to respond he
was referred to the author (IS). On admission to hospital,
his symptoms included poor appetite, weight loss of
5 kg, feeling useless, agitation and he was visibly slowed
down, leading to a diagnosis of major depression with
melancholic features.
Treatment with an increased dose of fluoxetine failed,
so a course of ECT was commenced. He rapidly improved
with ECT then plateaued and this was ceased after 15
treatments as he started to develop post-ECT confusion
and marked memory problems. He was commenced
on venlafaxine and discharged improved but not fully
recovered. His energy level, work capacity, sense of
humour and his libido were not as they had been. His
dose of venlafaxine was gradually increased to 375 mg
with little change. He never felt fully rested, he had to
constantly push himself at work and complained of a
dull aching fuzziness in his head.
He attributed the onset of his depression to the glau-
coma and began to wonder whether the eyedrops were
having an adverse effect. Ten months following his dis-
charge to reassure him the author (IS) made a literature
search and was surprised to discover reports of depres-
sion following timolol eye drops. Subsequently the treat-
ing ophthalmologist changed his drops to latanoprost.
Mr X. reported that his mood lifted within 48 h a cloud
lifted, the fuzzy feeling evaporated, and he began to feel
more energetic. After two weeks, both he and his wife
agreed that he was back to his normal self. He remained
on venlafaxine for another year and stopped it under
supervision. Three years after admission he remained
well.
Case 2
A 70-year-old married and retired scientist was
referred for treatment of his recurrent mood disorder by
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his treating psychiatrist. He had first experienced depres-
sion in his late 20s and had been treated with anti-
depressants. He had mostly been well and had worked
effectively until retirement 5 years ago. He described a
good marriage but they were not close and led somewhat
independent lives. He had been on lithium prophylaxis
for many years but this had been considered only partly
helpful in preventing recurrences. He had been treated
with tricyclic antidepressants, monoamine oxidase inhib-
itors, selective serotonin reuptake inhibitors and ECT in
the past.
His depressive symptoms included a loss of energy,
sleep disturbance, obsessional ruminations, social with-
drawal, anhedonia, loss of libido, loss of appetite but no
loss of weight. There was no guilt or psychotic symp-
toms. He was treated with venlafaxine and initially made
a good improvement but he remained symptomatic and
his mood fluctuated. His wife complained that he remained
anergic, uncommunicative and listless. Initially his dose
of venlafaxine was gradually increased to 375 mg but
this resulted in agitation without improvement in his
mood. Soon after the good result with case 1, the author
(IS) enquired about his glaucoma. He confirmed that
he was taking betaxolol eye drops (betaxolol 0.5%,
1 drop b.d.) and had been for the past 3 years. Again after
communication with his ophthalmologist and changing
to latanoprost he also reported a rapid improvement.
Discussion
The two case reports described above point to an asso-
ciation between topical betaxolol and clinical depres-
sion. Combined with other published data [4,5] and
previous reports for timolol, it appears that these beta-
blockers may cause depressive symptoms in some indi-
viduals. That betaxolol caused the depressive symptoms
cannot be proven conclusively, however, in each case
there is a clear temporal association between the com-
mencement of the eye drops and the onset of depressive
symptoms and the rapid recovery of mood following ces-
sation of the beta-blocker. In both cases the patients had
made a partial recovery with conventional antidepressant
treatment and it was only when the betaxolol eye drops
were withdrawn, that full recovery occurred.
It was first reported in 1967 that oral ingestion of beta-
blockers may cause depression. Subsequent investiga-
tions using prospective, case-matched studies have not
confirmed this. A recent publication has suggested that
beta-blockers may have been unjustly associated with
depression as previous studies had used antidepressant
prescriptions rather than diagnosis of depression in their
analysis. This was found to be a poor marker of depres-
sion by the more recent study [6]. The potential for
 I. SCHWEITZER, K. MAGUIRE, V. TUCKWELL
newly prescribed beta-blockers to cause depression was
not evaluated and thus not ruled out in this study as only
on-going beta-blocker use was investigated [6].
Theoretically, there are plausible pathophysiological
mechanisms by which beta-blockers could cause depres-
sion. Down-regulation of 1-adrenoceptors in the CNS
has been associated with the mechanism of action of
antidepressants, -adrenoceptors are increased in the
brains of suicide victims and in most valid animal model
of depression [7]. Interestingly, augmentation of antide-
pressant treatment with another beta-blocker pindolol
has recently received much attention. Many studies sug-
gest that this combination treatment leads to improve-
ment of otherwise refractory patients or a faster onset
of antidepressant action. The mechanism of action of
pindolol in this case has been attributed to its affinity for
5-HT receptors as it has been shown by positron emis-
sion tomography (PET) to occupy human 5-HT1A recep-
tors [8]. Betaxolol however, has negligible affinity for
5-HT receptors and has different effects to pindolol on
the actions of fluoxetine [9]. Thus although both drugs
are beta-blockers, one has the propensity to induce depres-
sion whereas the other may help to alleviate it.
The number of cases involved is small and points to
some patients being more susceptible than others. One
explanation may lie in the way individual patients metab-
olize particular beta-blockers. Timolol is metabolized by
the cytochrome P450 enzyme CYP2D6. Approximately
310% of the population lack normally active CYP2D6.
Edeki et al. [10] found that subjects lacking CYP2D6 had
greater systemic effects and higher plasma concentrations
of timolol following topical administration of timolol. In
the case of betaxolol, this may also be the explanation.
A minor metabolite of betaxolol, -hydroxylated betax-
olol, can be catalysed by CYP2D6. Further evidence for
this explanation comes from the observation that CNS
complaints were more common in those patients with
more profound decreases in intraocular pressure due pos-
sibly to higher drug concentrations [2].
These case reports add to the literature linking topical
ophthalmic -adrenoceptor antagonists with depression.
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571
While these cases are uncommon, this phenomenon
continues to be poorly recognized by the medical profes-
sion, psychiatrists, ophthalmologists and general prac-
titioners alike. Patients can be educated in techniques to
limit systemic absorption of topical agents and newer
formulations such as Beptoptic-S (Alcon Laboratories,
Frenchs Forest, NSW, Australia) have been designed to
limit drug exposure. Both will reduce the risk of adverse
effects, however, potentially dangerous side-effects
warrant careful monitoring by the prescribing physician.
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