Abstract
Beta-adrenoceptor antagonists (beta-blockers) are widely used as both systemic and topical medications. Topical ophthalmic beta-blockers are the treatment of choice in glaucoma and ocular hypertension management 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 levobunolol are the topical beta-blockers currently available in Australia.
Topical beta-blockers are systemically absorbed in small amounts from the nasopharyngeal mucousmembranes [1]. This can lead to adverse effects on the cardiovascular 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 accountedfor 17% of 369 central nervous system reactions to timolol reported to the National Registry of Drug-Induced 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 β1 adrenoceptor antagonist 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 administration 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 Australian Adverse Drug Reaction Advisory Committee have two reports of depression associated with betaxolol. This paper describes two further cases to alert the medical community to this continuing source of psychiatric morbidity.
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 disturbance and lack of libido. His general practitioner commenced 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 lossof 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 glaucoma and began to wonder whether the eyedrops were having an adverse effect. Ten months following his discharge to reassure him the author (IS) made a literature search and was surprised to discover reports of depression following timolol eye drops. Subsequently the treating 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 his treating psychiatrist. He had first experienced depression in his late 20s and had been treated with antidepressants. 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 inhibitors, selective serotonin reuptake inhibitors and ECT in the past.
His depressive symptoms included a loss of energy, sleep disturbance, obsessional ruminations, social withdrawal, anhedonia, loss of libido, loss of appetite but no loss of weight. There was no guilt or psychotic symptoms. 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 association between topical betaxolol and clinical depression. Combined with other published data [4], [5] and previous reports for timolol, it appears that these betablockers may cause depressive symptoms in some individuals. That betaxolol caused the depressive symptoms cannot be proven conclusively, however, in each case there is a clear temporal association between the commencement of the eye drops and the onset of depressive symptoms and the rapid recovery of mood following cessation 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 betablockers may cause depression. Subsequent investigations 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 depression by the more recent study [6]. The potential for 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 depression. Down-regulation of β1-adrenoceptors in the CNS has been associated with the mechanism of action of antidepressants, β-adrenoceptors are increased in the brains of suicide victims and in most valid animal model of depression [7]. Interestingly, augmentation of antidepressant treatment with another beta-blocker pindolol has recently received much attention. Many studies suggest that this combination treatment leads to improvement 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 affinityfor 5-HT receptors as it has been shown by positron emission tomography (PET) to occupy human 5-HT1Areceptors [8]. Betaxolol however, has negligible affinityfor 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 depression 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 metabolize particular beta-blockers. Timolol is metabolized by the cytochrome P450 enzyme CYP2D6. Approximately 3–10% 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, α-hydroxylated betaxolol, 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 possibly to higher drug concentrations [2].
These case reports add to the literature linking topical ophthalmic β-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. Patients can be educated in techniques to limit systemic absorption of topical agents and newer formulations such as Beptoptic-S (Alcon Laboratories, French's 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.