**5. Drug side effects and drug-drug interactions affecting serum sodium in patients being treated for psychiatric conditions**

#### **5.1 Antidepressants and non-steroidal anti-inflammatory drugs (NSAIDs) implicated in hyponatremia**

Among the classes of medications used to treat psychiatric conditions there are many side effects and interactions that may alter serum sodium. This is a critical consideration as many of the symptoms of hyponatremia, particularly generalized malaise and alterations in appetite can mimic symptoms of depression. A recent case report documented duloxetine induced hyponatremia, including symptoms such as "unsteady gait, dizziness, nausea, general malaise and poor appetite," resolved by discontinuing duloxetine [14]. Serotonin Norepinephrine Reuptake Inhibitors (SNRIs), such as duloxetine, have been associated with syndrome of inappropriate antidiuretic hormone (SIADH) with resulting hyponatremia. Hyponatremia results from an inappropriately high release of antidiuretic hormone (ADH) from the posterior pituitary, which results in an excess retention of water and a low serum osmolality. In particular SNRIs act primarily to inhibit the reuptake of both serotonin and noradrenaline, and in experimental models it has been shown that both serotonin and noradrenaline can result in the increased release of ADH (in rat models serotonin (5-HT) activated 5-HT1A receptors cause sympathoexcitation of 5HT1C and 5HT2 receptors and the release of ADH; also stimulation of the paraventricular and supraoptic nuclei with norepinephrine can increase release of ADH within the serum) [14]. Therefore, through these mechanisms it is hypothesized that SNRIs cause SIADH in patients, a life-threatening side effect that must be monitored for by clinicians.

A case report of a patient diagnosed with schizophrenia, taking desmopressin and meloxicam identified that NSAIDs can significantly augment hyponatremia

by "increas[ing] water retention" [15]. Notably, the worsened water retention is particularly problematic for patients on desmopressin, and complete resolution of symptoms occurred after desmopressin was tapered and meloxicam stopped, with normalization in plasma sodium [15] (**Figure 1**, used with permission from authors).

### **5.2 Other medications and interactions implicated in hyponatremia**

Fabrazzo et al. [16] discuss three cases involving delorazepam, olanzapine and fluvoxamine, respectively, in which patients with various presentations of bipolar disorder were hospitalized, and hyponatremia was discovered on admission. Workup revealed SIADH. Multiple interventions were trialed, including administration of hypertonic saline, and decreasing doses of various medications. It was not until the offending medications were removed that patients demonstrated resolution of their hyponatremia. Notably, olanzapine, fluvoxamine and delorazepam were being administered in conjunction with other medications that may have contributed to the hyponatremia. In the case of the patient taking delorazepam, they also were prescribed oxcarbazepine, which ultimately was replaced with gabapentin. In the case of the patient taking olanzapine, he also was taking delorazepam and oxcarbazepine. Likewise, the patient on fluvoxamine was also taking oxcarbazepine. These medications in conjunction with one another appear to have an additive property on hyponatremia.
