Introduction
Pharmacological management of depression in the elderly is difficult to achieve because of increased iatrogenic risk related to higher frequency of side effects or drug–drug interactions. Newer antidepressants such as selective serotonin reuptake inhibitors (SSRIs) appear to be less toxic. However, risk of serotonin syndrome should be taken into account because its incidence is increasing with the rise in SSRI prescriptions (Boyer and Shannon, Reference Boyer and Shannon2005). Indeed, a recent study showed that 25% of patients aged over 65 years taking antidepressants are also under another drug that could have been responsible for a major interaction (Mark et al., Reference Mark, Joish, Hay, Sheehan, Johnston and Cao2010).
We report a case of serotonin syndrome associated with hyponatremia which occurred in an old patient, following association of low doses of escitalopram (named Cipralex® in the UK, Seroplex® in France) with a new formulation of miconazole, the gingival mucoadhesive tablet (Loramyc® in UK and France).
To our knowledge, this is the first observation of serotonin syndrome consecutive to the combination of both molecules. Few pharmacokinetic studies of the miconazole gingival mucoadhesive tablet are available, and this drug's interaction with escitalopram has never been reported before. Here, we provide some data that may support the hypothesis of such serious interaction.
Case report
An 88-year-old woman presented to our geriatrics department in April 2010 with anorexia and apathy. Her medical background included hypothyroidism treated with L-thyroxin, cataract and glaucoma treated with timolol and travoprost. On physical examination, we noted the presence of a major depressive episode associated with oral candidiasis. Laboratory tests did not find any inflammation, neither electrolyte disturbance nor metabolic disorder, and thyroid-stimulating hormone (TSH) was normal. As a result, low doses of escitalopram (5 mg/d) associated with local antifungal therapy by miconazole mucoadhesive gingival tablet (50 mg/d) were prescribed.
Forty-eight hours after administration of treatments, the patient presented with drowsiness, confusion, hypertonia, and tremors of all four limbs, leading to hospitalization. Clinical examination evidenced no fever, tachycardia at a rate of 110 beats per minute, high blood pressure of 180/100 mmHg, and increased reflexes associated with bilateral extrapyramidal hypertonia. Laboratory tests revealed severe hyponatremia, with a serum sodium concentration of 123 mmol/L.
Serotonin syndrome was suspected. Escitalopram and miconazole were immediately stopped. Neuropsychological symptoms subsided spontaneously in three days, and serum sodium came back to normal in six days associated with fluid restriction.
Using the Naranjo Adverse Drug Reaction probability scale, which is not specifically intended for drug interactions, serotonin syndrome was a probable adverse reaction associated with the combination of escitalopram and miconazole in our patient (Naranjo et al., Reference Naranjo1981).
Discussion
Serotonin syndrome is a rare but potentially lethal consequence of central and peripheral serotonin receptors’ excessive stimulation (5-HydroxyTryptamine = 5-HT). Several mechanisms may be responsible for this hyperstimulation: blockade of serotonin reuptake (tricyclic antidepressants, SSRIs, synthetic opioids), its exaggerated release in the synaptic cleft (triggered by cocaine, amphetamines), increased synthesis (by augmentation of its precursor L-tryptophan) or decreased catabolism (caused by monoamine oxidase inhibitors), hypersensitivity of its postsynaptic receptors (induced by lithium), and action of serotonin agonists (buspirone) (Jacob and Spinler, Reference Jacob and Spinler2006). In the absence of a relevant paraclinical test, diagnosis is based on clinical evidences. Prior introduction or dose modifications of SSRI treatment are often part of medical history. Onset of symptoms is usually fast (minutes to hours). Physical signs include delirium, neuromuscular disorders (hypertonia, hyperreflexia, clonus), sometimes fever (by thermogenesis), and sympathicotonia (psychomotor agitation, tachycardia, hypertension, sweating, tremors, mydriasis, xerostomia). Their intensity can range from mild to severe, with a lethal risk, correlating with nervous system levels of serotonin activity. This state will stay unrelieved if intoxication persists, or will be transient and regress in days following discontinuation of the causative agent. No biological test is recommended for diagnosis, although a correlation between symptoms and plasma levels of serotonin have been reported, normal doses of SSRI cannot rule out the diagnosis. This condition is essentially treated by discontinuation of the causative agent. Administration of benzodiazepines can be useful for managing neuromuscular manifestations, hyperthermia, and hyperadrenergic syndrome. 5-HT2A antagonists such as cyproheptadine failed to prove their efficacy.
Escitalopram is a selective inhibitor of serotonin reuptake, which acts by raising serotonin levels within synapses of the central nervous system. Considered to be the most selective SSRI due to its minimal effects on norepinephrine and dopamine reuptake, only a few reported cases described escitalopram-induced serotonin syndrome. It is mainly metabolized via hepatic CYP2C19, but also via both CYP3A4 and CYP2D6. Interactions are on one hand pharmacodynamic, due to association with drugs that could increase serotonergic activity, and on the other hand pharmacokinetic with drugs acting on cytochrome P450 enzymes responsible for escitalopram metabolism.
Miconazole is an antifungal azole, which acts by impairing fungal ergosterol biosynthesis through inhibition of the cytochrome P450 14α-demethylase. Because of its broad spectrum, miconazole is active on all Candida species. In vitro studies have shown miconazole to be a strong inhibitor of many drug-metabolizing cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) (Niwa et al., Reference Niwa, Inoue-Yamamoto, Shiraga and Takagi2005a; Reference Niwa, Shiraga and Takagi2005b). When miconazole is used topically as oral gel or buccal tablets, risks for drug interactions are reduced in comparison with systemic use. Nonetheless, clinical cases have shown that the oral dosage gel formulation still has a systemic diffusion, which is responsible of significant interactions (Pemberton et al., Reference Pemberton, Oliver and Theaker2004). Occurrences of anticoagulant overdose (antivitamin K) have been related to enzyme inhibition by miconazole (Ortín et al., Reference Ortín, Olalla, Muruzábal, Peralta and Gutiérrez1999), and a comparable increase has also been observed with exposure to etoricoxib (Hynninen et al., Reference Hynninen, Olkkola, Neuvonen and Laine2009). This important risk of interactions resulted in discontinuation of miconazole prescriptions by a majority of physicians.
This in turn led the pharmaceutical industry to propose a new formulation of miconazole: the gingival mucoadhesive tablet, which could be used in case of oropharyngeal candidosis in immunocompromised patients (Lalla and Bensadoun, Reference Lalla and Bensadoun2011). A pharmacokinetic study of 18 young and healthy volunteers explored systemic absorption of miconazole after local administration using oral gel (375 mg/d) or gingival mucoadhesive tablet (50 and 100 mg/d). Systemic absorption of miconazole (plasma miconazole concentration >0.4 μg/mL and <1 μg/mL) has been found in 27% (5 patients out of 18 studied) of patients with oral gel and in 16% (3 patients out of 18 studied) of patients with the gingival mucoadhesive tablet (Cardot et al., Reference Cardot, Chaumont, Dubray, Costantini and Aiache2004).
Various factors might enhance greater systemic absorption in older adults than in healthy volunteers (oral mucosa inflammation, as in oral candidiasis, changes in hydration of mucous membranes, in oral pH, potential increased sublingual absorption, or possible cognitive disorders which would promote the swallowing of mucoadhesive tablets). Subsequently, the host's cytochrome P450 isoenzymes may also be inhibited by miconazole, including those responsible for the metabolism of escitalopram (CYP2C19, CYP3A4, and CYP2D6). This mechanism provides a plausible explanation for the suspected drug–drug interaction we report.
Nevertheless, our observation has some limitations. First, we did not look for genetic polymorphisms in the metabolizing enzymes for escitalopram, but we hypothesized that such polymorphisms could not rule out the possibility of a drug–drug interaction and might just act as a sensitizing mechanism for escitalopram overdose due to cytochrome inhibition by miconazole. Second, case reports generate hypotheses only as no conclusions regarding causality or association can be made. Moreover, rechallenge of escitalopram could not be performed in our patient due to potential lethal consequences.
Finally, to our knowledge, pharmacokinetic studies about the miconazole mucoadhesive tablet have not included older adults. Yet, it is necessary to evaluate systemic absorption of this new formulation in such populations.
As a consequence, one should be cautious when prescribing miconazole mucoadhesive tablet in association with escitalopram, as the latter has a relatively narrow therapeutic index, particularly in the elderly.
Conclusion
To our knowledge, pharmacokinetics of gingival mucoadhesive miconazole tablet in elderly people has not previously been analyzed. Therefore, and due to multiple factors that can add and modify systemic absorption of this new formulation of miconazole, risks of drug interactions remain poorly defined in this population. Consequently, prescription of this antifungal drug should be made with caution in the elderly, especially when coprescribed with molecules metabolized by cytochromes P450 isoenzymes, as escitalopram. Thus, it seems necessary to study and accurately determine systemic absorption of this new dosage of miconazole in older adults.
Conflict of interest
None.
Description of authors' roles
G. Baptista supervised the data collection and wrote the article. C. Eiden assisted in writing the article. P. Monguillot & C.Philibert collected the data. C. Jeandel assisted in writing the article.
