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Recurrent Hyponatremia Associated With Citalopram and Mirtazapine

2006; Elsevier BV; Volume: 48; Issue: 4 Linguagem: Inglês

10.1053/j.ajkd.2006.07.011

1523-6838

Nüket Bavbek, Ayşe Kargılı, Ali Akçay, Arif Kaya,

Bipolar Disorder and Treatment

Depression is a common problem in elderly patients and frequently is treated with antidepressants. We present the case of a 67-year-old depressed woman who began treatment with citalopram. Two months later, hyponatremia was diagnosed, most likely syndrome of inappropriate antidiuretic hormone secretion. After discontinuation of citalopram therapy, serum sodium concentrations normalized. Later, she began treatment with mirtazapine. Five months after initiating mirtazapine therapy, she developed symptomatic hyponatremia. After mirtazapine therapy was discontinued, serum sodium concentrations normalized. In this case, unlike those previously reported, hyponatremia recurred 5 months after switching from citalopram to mirtazapine, which is believed to be a safe antidepressant. In conclusion, patients older than 60 years should have baseline electrolyte measurements before starting therapy with an antidepressant, and these should be monitored not only in the first weeks of treatment, but throughout the full course. Depression is a common problem in elderly patients and frequently is treated with antidepressants. We present the case of a 67-year-old depressed woman who began treatment with citalopram. Two months later, hyponatremia was diagnosed, most likely syndrome of inappropriate antidiuretic hormone secretion. After discontinuation of citalopram therapy, serum sodium concentrations normalized. Later, she began treatment with mirtazapine. Five months after initiating mirtazapine therapy, she developed symptomatic hyponatremia. After mirtazapine therapy was discontinued, serum sodium concentrations normalized. In this case, unlike those previously reported, hyponatremia recurred 5 months after switching from citalopram to mirtazapine, which is believed to be a safe antidepressant. In conclusion, patients older than 60 years should have baseline electrolyte measurements before starting therapy with an antidepressant, and these should be monitored not only in the first weeks of treatment, but throughout the full course. SELECTIVE SEROTONIN REUPTAKE inhibitors have gained widespread use in elderly depressed patients because of their favorable adverse-effect profile. However, selective serotonin reuptake inhibitors have been associated increasingly with syndrome of inappropriate antidiuretic hormone (ADH) secretion. The risk for developing hyponatremia while administered a selective serotonin reuptake inhibitor seems to increase with age, female sex, previous history of hyponatremia, and concomitant use of other medications known to cause hyponatremia.1Bouman W.P. Pinner G. Johnson H. Incidence of selective serotonin reuptake inhibitor induced hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion in the elderly.Int J Geriatr Psychiatry. 1998; 13: 12-15Crossref PubMed Scopus (119) Google Scholar, 2Wilkinson T.J. Begg F.J. Winter A.C. Sainsbury R. Incidence and risk factors for hyponatremia following treatment with fluoxetine or paroxetine in elderly people.Br J Clin Pharmacol. 1999; 47: 211-217Crossref PubMed Scopus (136) Google Scholar There is no previously reported case describing an association between hyponatremia and rechallenge of citalopram or mirtazapine, which is known to be a safe antidepressant. Mirtazapine inhibits α2 autoreceptors and heteroreceptors, blocks 5-hydroxytryptamine type 2 (5-HT2) and 5-HT3 receptors, and acts through noradrenergic and 5-HT1A receptors. The German multicenter drug surveillance program Arzneimittelsicherheit in der Psychiatrie that assesses severe or new adverse drug reactions in psychiatry reported that in 53,042 patients treated with antidepressants, mirtazapine was connected with no patient with significant hyponatremia.3Degner D. Grohmann R. Kropp S. et al.Severe adverse drug reactions of antidepressants: Results of the German multicenter drug surveillance program AMSP.Pharmacopsychiatry. 2004; 37: 39-45Crossref Google Scholar In our MEDLINE search, we could find only 1 patient report of hyponatremia with mirtazapine use.4Roxanas M.G. Mirtazapine induced hyponatremia.Med J Aust. 2003; 179: 453-454PubMed Google Scholar We present the case of a 67-year-old patient who developed hyponatremia 5 months after switching from citalopram to mirtazapine therapy. A 67-year-old woman with Parkinson disease was admitted to our hospital, reporting abdominal pain, nausea, vomiting, decreased food intake, and agitation for 7 days. Approximately 2 months earlier, the patient had started treatment with citalopram, 20 mg/d, for depression. The patient’s medication regimen before admission also included levodopa. On arrival, the patient’s temperature was 36.8°C, blood pressure was 135/85 mm Hg, and pulse was 80 beats/min. She appeared euvolemic without evidence of congestion or dehydration. She had decreased ability to show facial expressions (mask appearance), bradykinesia, and tremors at rest. Significant laboratory findings included the following: sodium, 110 mEq/L (110 mmol/L); potassium, 4.5 mEq/L (4.5 mmol/L); chloride, 83 mEq/L (83 mmol/L); blood urea, 24 mg/dL (4 mmol/L); creatinine, 0.5 mg/dL (44 μmol/L); glucose, 71 mg/dL (3.9 mmol/L); and serum osmolarity, 245 mOsm/L. Urine sodium and osmolarity were 148 mEq/L (148 mmol/L) and 380 mOsm/kg (380 mmol/kg), respectively. Values for morning cortisol, thyroid-stimulating hormone, and free thyroxin were within normal limits. The diagnosis of syndrome of inappropriate ADH secretion in this patient was made based on hyponatremia and low serum and high urine osmolalities. No other cause of hyponatremia, including diuretic therapy, tumors, and respiratory system disease, were present. Citalopram treatment was discontinued, and hypertonic saline was infused. Hyponatremia was corrected by treatment with hypertonic saline at 2 mEq/L/h until resolution of symptoms.5Thurman J.M. Therapy of dsynatremic disorders.in: Brady H.G. Therapy in Nephrology and Hypertension. (ed 2). WB Saunders, Spain2003: 335-348Google Scholar Symptoms resolved immediately after correction of hyponatremia. Anticipating the possibility of additional hyponatremia, mirtazapine, 15 mg nightly, half the recommended starting dose, was prescribed, and the patient subsequently was discharged. A follow-up sodium level 3 weeks after discharge was normal. Five months after discharge, the patient was admitted again to our hospital with a 2-day history of nausea and intermittent vomiting. She was afebrile, with normal vital signs. She had facial mask appearance, bradykinesia, and tremors at rest. Laboratory studies showed the following values: serum sodium, 115 mEq/L (115 mmol/L); potassium, 3.8 mEq/L (3.8 mmol/L); chloride, 86 mEq/L (86 mmol/L); blood urea, 18 mg/dL (3 mmol/L); creatinine, 0.5 mg/dL (44 μmol/L); and glucose, 98 mg/dL (5.4 mmol/L). Urine sodium was 249 mEq/L (249 mmol/L), serum osmolarity was 265 mEq/L, and urine osmolarity was 386 mOsm/kg (386 mmol/kg). Mirtazapine therapy was discontinued, and the patient was treated with hypertonic saline at 2 mEq/L/h until resolution of symptoms. Symptoms resolved with correction of hyponatremia. She was discharged when serum sodium levels returned to normal with tianeptine prescription. Her follow-up sodium levels are normal in her 2- and 4-week controls since discharge. Correction of the patient’s hyponatremia, combined with discontinuation of both citalopram and mirtazapine therapy, resulted in resolution of hyponatremia. Most cases of drug-induced hyponatremia involve elderly patients, which could be related to the altered ADH regulation or action of ADH on kidneys. Impairment of the maximal diluting and concentrating ability of the kidney6Kazal L.A. Hall D.L. Miller L.G. Noel M.L. Fluoxetine-induced SIADH: A geriatric recurrence?.J Fam Pract. 1993; 36: 341-343PubMed Google Scholar, 7Lindeman R.D. Van Buren H.C. Raisz L.G. Osmolar concentrating ability in healthy young men and hospitalized patients without renal disease.N Engl J Med. 1960; 262: 1306-1309Crossref PubMed Scopus (64) Google Scholar and increased ADH secretion also might contribute. Another possible explanation for the propensity for hyponatremia in the elderly is their increased ADH response to osmolar stimuli compared with young control patients.8Miller M. Fluid and electrolyte balance in the elderly.Geriatrics. 1987; 42 (71, 75-76): 65-68PubMed Google Scholar The finding of syndrome of inappropriate ADH secretion secondary to citalopram use may reflect dysregulation of serotoninergic control of ADH release or metabolism. Experimental evidence in rodents showed the presence of serotonin neurons in the hypothalamic supraoptic nucleus, where the ADH prohormone is synthesized.9Vacher C.M. Fretier P. Creminon C. Calas A. Hardin-Pouzet H. Activation by serotonin and noradrenaline of vasopressin and oxytocin expression in the mouse paraventricular and supraoptic nuclei.J Neurosci. 2002; 22: 1513-1522PubMed Google Scholar Another study suggested that serotonin may be involved in the regulation of ADH release.10Jorgensen H. Riis M. Knigge U. Kjaer A. Warberg J. Serotonin receptors involved in vasopressin and oxytocin secretion.Neuroendocrinology. 2003; 15: 242-249Crossref Scopus (147) Google Scholar The mechanism of hyponatremia in patients administered mirtazapine is thought to be through α1 or serotonergic stimulation of ADH, but other possible causes include increased osmoreceptor sensitivity, decreased renal ability to conserve salt and water in the elderly, enhanced renal action of ADH,11Helderman J.H. Vestal R.E. Rowe J.W. et al.The response of arginine vasopressin to intravenous ethanol and hypertonic saline in man: The impact of aging.J Gerontol. 1978; 33: 39-47Crossref PubMed Scopus (240) Google Scholar and decreased metabolism of the antidepressant. In conclusion, mirtazapine use should be considered in the differential diagnosis of hyponatremia, as well as citalopram use. Patients older than 60 years should have baseline electrolyte measurements before starting therapy with an antidepressant, and these should be monitored not only in the first weeks of treatment, but throughout the full course.