INTRODUCTION
Mental health problems have been increasing worldwide in recent years. Thus, an inevitable increase in the consumption of antidepressants is expected soon, which is predicted to be much greater than that observed at the beginning of the current century.
1,2) Simultaneously, increased rates of clinically important side effects of new and old psychiatric drugs will also occur. Drug-induced hyponatremia was previously reported after the administration of fluoxetine, sertraline, paroxetine, and fluvoxamine
3) and has also recently been described for escitalopram, a new selective serotonin reuptake inhibitor (SSRI).
The prevalence of hyponatremia among hospitalized older adult (age >75 years) patients ranges from 11.6% to 42.6%
4,5) and up to 22.5% among patients in long-term care facilities.
6) Hyponatremia leads to a lack of stability, frequent uncontrolled falls, bone fractures, and deterioration of cognitive functioning.
1) Although a serum sodium level (SSL) of 135 mmol/L is considered within the normal range, increased hospital mortality is observed for levels below 138 mmol/L.
5) Moreover, managing hyponatremia can be challenging due to a variety of potential causes (
Table 1). Thus, this condition should be distinguished from other ailments such as motoric cognitive risk syndrome, which is common among older adults and may also manifest in falls.
7) Our report highlights the possible life-threatening side effects of seemingly safe medications that are widely used in clinics.
DISCUSSION
We present two case reports of women aged 85 and 84 years, respectively, who developed hyponatremia, most likely after escitalopram administration (escitalopram-induced syndrome of inappropriate secretion of antidiuretic hormone [SIADH]). The lack of symptoms of hypervolemia at the time of initial diagnosis excluded kidney, thyroid, cardiovascular, and adrenal cortex disorders, as well as neoplasms as other possible explanations.
A few types of SIADH have been described in the literature. First, syndromes associated with excessive ADH production are usually caused by antidepressants (SSRIs, SNRIs, serotonin and noradrenaline reuptake inhibitors, and tricyclic antidepressants [TCAs]), antipsychotics, antiepileptics, and antineoplastic drugs.
1,6,8) Furthermore, many drugs, including carbamazepine, cyclophosphamide, and nonsteroidal anti-inflammatory drugs, can induce hyponatremia by the peripheral receptor effect rather than by stimulating the secretion of the hormone itself.
8) Moreover, reset osmostat (RO) SIADH in older adults might also occur due to alterations in osmoreceptor cell metabolism.
9) The condition is frequently observed in residents of long-term care facilities with simultaneous quadriplegia, psychosis, cerebral hemorrhage, dementia with Lewy bodies, alcoholism, malnutrition, malignancy, and infections.
9) Lastly, hyponatremia after the administration of thiazide or thiazide-like diuretics can occur in up to 30% of older adult patients.
10) Advanced age, female sex, and low body mass index have been identified as risk factors for the development of thiazide-associated hyponatremia.
Establishing an exact diagnosis for the first patient was challenging because of the use of multiple drugs that could cause SIADH (memantine, quetiapine, and doxepin).
8,11) In the second patient, hyponatremia seemed to be more directly connected with the use of escitalopram owing to the lack of other diseases or drugs that could contribute to the development of SIADH. SSRI-induced SIADH is one of the most common mechanisms of hyponatremia in older adults, although only 14 cases of escitalopram-induced SIADH have been described in the literature.
1,11,12) However, it must be emphasized that in the presented cases, even small doses of escitalopram (5 mg) caused serious side effects. In other reports, the doses of escitalopram were usually 10 mg.
11) Recent reports suggest a lower risk of hyponatremia with the use of TCAs and noradrenergic and specific serotonergic antidepressants compared to SSRI and SNRI; thus, changing SSRI to TCA (doxepin) might have been reasonable.
12,13)
In both patients, the hyponatremia did not resolve after escitalopram withdrawal or standard treatment. In the second patient, SSL normalization was achieved after treatment with fludrocortisone acetate. According to the available data, the SSL should normalize approximately 2 weeks after SSRI discontinuation and the introduction of limited fluid intake and sodium chloride supplementation (as stated by guidelines).
6,13) However, despite this treatment, hyponatremia persisted in our patients for months. Abnormal homeostatic mechanisms, such as RO syndrome, may explain the observed resistance to treatment. This theory is supported by the fact that hyponatremia due to RO does not respond to fluid restriction (as non-RO SIADH hyponatremia), oral sodium supplementation, or fludrocortisone treatment.
9) Another explanation could be adrenal insufficiency or mineralocorticoid-responsive hyponatremia of the elderly (MRHE), which requires the exclusion of SIADH and adrenal dysfunction.
14) MRHE is considered a mildly hypovolemic hyponatremia caused by renal sodium loss. Age-related decreased sodium reabsorption by proximal renal tubules and hyporesponsiveness of the renin-angiotensin-aldosterone system may cause constantly increased urinary sodium excretion. Decreased sodium retention leads to volume depletion, which causes elevation of plasma antidiuretic hormone levels. The recommended treatment for MRHE is, instead of water restriction, which may worsen hyponatremia, an administration of mineralocorticoids such as fludrocortisone acetate. Unfortunately, both fludrocortisone treatment and dietary sodium chloride supplementation may be limited by an increase in BP.
In conclusion, managing hyponatremia in older adults is complex. Regular monitoring of SSLs should be mandatory in this population, particularly following the initiation of antidepressants or thiazides. Unfortunately, due to the unpredictability of drug-related hyponatremia, the timing or frequency of such monitoring cannot be precisely defined and should be based on clinical experience. In addition to informing patients and their caregivers of the potential risks of hyponatremia, preventive fluid moderation or restriction and ordering SSL assessment should be considered. Treatment of hyponatremia requires a multimodal approach that considers patient comorbidities and pharmacotherapy. However, despite the best care, it can last for months. Reporting side effects, especially of the most popular drugs to the local center for drug monitoring, is crucial in terms of increasing our awareness of the benefits of our patients.