Beware of serotonin overload in pharmacotherapy for elderly patients with burning mouth syndrome

Abstract

Dear Editor, Elderly patients taking antidepressants may be brought to the emergency room with an emergency serotonin overload condition such as serotonin syndrome or self-injurious behaviour. I read with interest the report by Fukushima et al. on self-injurious behaviour in an elderly patient with burning mouth syndrome (BMS). I would like to point out that this could be prevented by paying attention to drug interactions and doses of antidepressants. Taking up the case of Fukushima et al., an elderly BMS patient was treated with amitriptyline 30 mg/day, sulpiride 150 mg/day, and some herbal medicines along with general psychotherapy. However, the glossalgia did not disappear and became persistent, so paroxetine 20 mg/day was added. The patient then cut off the tip of her tongue with scissors. There are potential problems with this combination therapy. Amitriptyline, sulpiride, and paroxetine are all mainly metabolised by cytochrome P450 2D6 (CYP2D6) in the liver. Paroxetine has the highest inhibitory constant for the CYP2D6 isoenzyme of all antidepressants (Ki = 0.065–4.65 μmol). This high affinity explains its high inhibitory interaction profile with substrates for CYP2D6. Paroxetine’s potent CYP2D6 inhibition also implies significant inhibition of the metabolism of CYP2D6 substrates including amitriptyline and paroxetine, and increase in their serum levels, causing excess serotonin in the patient’s brain. As a result, the patient’s impulsiveness increased, and oral selfmutilation of cutting the tongue may have emerged. BMS is a chronic intraoral burning sensation or dysesthesia without clinically evident causes, which can lead to a significant disease burden. More than half of the patients with BMS are older than 50 years, and some of them have comorbid depression and anxiety. Pharmacotherapy for BMS is mainly based on tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and selective serotonin reuptake inhibitors, which stimulate descending pain inhibitory pathways via serotonergic neurotransmission. However, the effectiveness of single-agent pharmacotherapy is limited, and skilful polypharmacy is currently being used to reinforce it. Therefore, the occurrence of side effects due to drug–drug interactions and agerelated decreases in drug metabolism should be considered. In our study, the concentration of amitriptyline in BMS was found to be effective at doses as low as 10–20 mg/day, and higher doses were associated with increased side effects. The mean effective dose of amitriptyline in BMS patients older than 75 years is 13.2 5.8 mg/day, and the therapeutic dose of amitriptyline may be lower in older BMS patients than in younger patients. A polymorphism in the CYP2D6 gene (CYP2D6*10 allele) has been shown to significantly increase plasma paroxetine concentrations in a Japanese population, so a genetic polymorphism with low CYP2D6 activity may further increase serotonin levels in the patient’s brain. Although much less than the effects of genetic polymorphisms, the enzymatic activity of CYP2D6 also declines with age, so that drug metabolism of antidepressants is further reduced in older age. In conclusion, pharmacotherapy for elderly patients with BMS requires special attention to drug interactions and doses of antidepressants to avoid impulsivity caused by serotonin excess.