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Clinical Researcher, Department of Internal Medicine, San Camillo Hospital, Circonvallazione Gianicolense, 00152 Rome, Italy, fax 06-58704209, gfamularo{at}scamilloforlanini.rm.it
Clinical Researcher, Department of Internal Medicine, San Camillo Hospital
Clinical Researcher, University Campus Biomedico, Rome
Clinical Researcher, Department of Internal Medicine, San Camillo Hospital
Published Online, May 12, 2009. www.theannals.com, DOI 10.1345/aph.1L724
Case Report. A 76-year-old woman was prescribed mirtazapine 30 mg daily for depression. At that time, her serum sodium level was 142 mEq/L (reference range 135-149). Hypertension had been managed for 3 years with telmisartan and hydrochlorothiazide and she was not taking any other medications, including over-the-counter and recreational drugs and herbal remedies.
Two months later the patient presented with a 2-day history of worsening lethargy and confusion; sodium levels were 144 mEq/L 3 weeks prior to presentation. Physical and neurologic examination showed only drowsiness and severe dysphasia; weight was 56.3 kg. A brain computed tomography (CT) scan was unrevealing, serum sodium was 114 mEq/L with osmolality 236 mOsmol/kg (reference range 280-300), and urine osmolality was 450 mOsmol/kg (50-1300). The remaining variables, including thyroid and adrenal function tests, were normal; 24-hour urinary sodium excretion was 280 mEq/day (100-260) while the patient was not on salt restriction. Mirtazapine, telmisartan, and hydrochlorothiazide were withdrawn, hypertonic (3%) saline was infused (1 mL/kg/h) for 12 hours followed by isotonic (0.9%) saline for another 36 hours, and her mental status progressively improved, with serum sodium rising to 122 mEq/L after 10 hours and 131 mEq/L after 24 hours. On day 2, she was fully alert, with no dysphasia or other neurologic abnormality. Weight was 55.9 kg and serum sodium was 145 mEq/L. A chest CT scan was normal. On day 5, she was discharged on telmisartan 80 mg daily and was advised against taking mirtazapine or other serotonergic antidepressants.
Discussion. Use of the Naranjo probability scale suggests a probable causal relationship between exposure to mirtazapine and onset of hyponatremia.2 Mirtazapine acts centrally through enhancing noradrenergic and serotonergic activity and is commonly prescribed for elderly persons with mood disorders.3 Its safety profile is favorable; mild sedation, constipation, dry mouth, increased liver enzyme levels, and weight gain are relatively common adverse effects.1
Mirtazapine-induced hyponatremia has been reported in very few patients. In most cases, subjects were older than 60 years or treated for a mean of 6 days (range 6-150).4 Our patient was elderly and was receiving mirtazapine 30 mg daily for more than 2 months when hyponatremia was recognized. However, doses as low as 7.5 mg daily and a treatment duration of several months have also been linked to a definite risk of hyponatremia.4 The possibility of delayed-onset hyponatremia suggests that serum sodium and antidiuretic hormone (ADH) should be monitored for several months, and perhaps indefinitely, after mirtazapine is started.
Serotonergic stimulation of ADH release, increased osmoreceptor sensitivity, and enhanced renal action of ADH may explain mirtazapine-induced hyponatremia.4 However, we recognized many features of the syndrome of inappropriate ADH secretion, such as the decreased serum osmolality paralleled by increased urinary osmolality, the absence of any signs of excessive or depleted volume of extracellular fluid, and the mildly increased urinary sodium excretion above the cut-off level of 40 mEq/L paralleled by normal thyroid and adrenal function. Whether abnormal salt handling by renal tubules might represent an additional mechanism of hyponatremia with mirtazapine is unclear. Hydrochlorothiazide could have contributed to the onset of hyponatremia in this patient, for example, the finding of urinary sodium excretion that was just above normal after such a long period of diuretic therapy. The patient was also taking telmisartan; however, no interaction between mirtazapine and telmisartan or other angiotensin II receptor antagonists is known to cause hyponatremia.5
Clinicians should be aware of the possibility of delayed-onset hyponatremia during treatment with mirtazapine. Close serum sodium monitoring is needed, particularly among the elderly, who have additional risk factors for hyponatremia.
References
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