An unusual presentation of dose dependent SIADH secondary to mirtazapine therapy

To the Editor

A 77-year-old male with a diagnosis of Moderate Depressive Episode was treated with escitalopram (increased to 20 mg/day). The initial investigations were within normal limits. In view of partial improvement, mirtazapine was added as an adjuvant and increased to 15 mg/day. The patient tolerated the combination well with further improvement in depressive symptoms. After around 4 weeks, the dose of mirtazapine was increased to 30 mg/day. The next day, he developed confusion, nausea and vomiting, and the investigations revealed sodium, 122 mEq/dL; uric acid, 2.8 mg/dL; blood urea nitrogen (BUN), 8 mEq/dL; urinary sodium, 54 mEq/L; and serum osmolarity, 260 mOsm/kg of water. The serum cortisol, thyroid profile, chest X-ray, magnetic resonance imaging (MRI) brain and cerebrospinal fluid (CSF) analysis was normal. The patient was diagnosed with Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), and mirtazapine was stopped. He was treated with water restriction and salt diet, and within 3 days, his symptoms resolved and sodium levels became normal. The patient was continued on escitalopram and achieved remission after around 3 months of treatment.

Discussion

The current case highlights the possibility of SIADH developing as a dose dependent adverse effect of mirtazapine therapy. On the Naranjo Adverse Drug Reaction Probability Scale, the score of index case was 7, which suggests a probable association of SIADH and mirtazapine (Naranjo et al., 1981).

Although multiple antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), are known to cause SIADH, there have been only few reports of SIADH and one report of dose related SIADH with mirtazapine therapy (Ghosh et al., 2014). Also usually the antidepressant induced SIADH occurs within 1 month of initiation of drug and is not dose dependent (Liu et al., 1996). However, in the current case, the side effect appeared late and was dose related. The mechanism appears to be serotonin mediated release of antidiuretic hormone (ADH) from supraoptic nuclei (Liu et al., 1996). In the index case, the presence of risk factors like old age and concomitant use of a serotonin and norepinephrine reuptake inhibitor (SNRI) could have predispoded to the development of SIADH. The current case highlights the need of caution while using higher dosages of mirtazapine, particularly in elderly patients. Also caution must be exercised while combining mirtazapine with drugs which have serotonergic action. Further studies would be required to establish with confidence whether the SIADH secondary to mirtazapine is always dosage dependent. Also, the case suggests the need to do routine sodium levels monitoring while increasing dosages of mirtazapine, especially in older age group.