Hyponatremia and SIADH

Hypotonic hyponatremia (often defined as a serum sodium level <130 or 135 mmol/L, depending on the study) has been reported in association with numerous psychotropic agents, including bupropion, carbamazepine, divalproex, lithium, lamotrigine, MAOIs, oxcarbazepine, SSRIs, SNRIs (including duloxetine and venlafaxine), mirtazapine, tertiary amine TCAs, other norepinephrine reuptake inhibitors such as reboxetine, and most FGAs and SGAs. Hyponatremia that has been observed to occur during treatment with an SSRI (citalopram) has been shown to recur after substitution with an SNRI (duloxetine). The mechanism(s) by which antidepressants can cause increased release of hypothalamic antidiuretic hormone (ADH), causing water retention and serum hypo-osmolarity, are not well understood. SIADH may be three times more likely among patients taking SSRIs than among patients taking other antidepressants (Movig et al. 2002). A review of relative risks for SIADH among antidepressants suggests that mirtazapine and tricyclics may be less likely than other antidepressants to cause SIADH (De Picker et al. 2014). Case reports also exist of antipsychotic-associated hyponatremia leading to NMS (Spigset and Hedenmalm 1995).

Known patient-specific risk factors for psychotropic-induced hyponatremia include the following (Spigset and Hedenmalm 1995):

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  Increasing age (especially >65 years)

  
  
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  Female sex

  
  
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  Smoking (because nicotine increases antidiuretic hormone [ADH] secretion)

Mechanisms by which psychotropic drugs may cause SIADH are not well understood, although one proposal is that SSRIs may cause release of ADH or renal responsiveness to ADH. However, as noted earlier, nonserotonergic drugs such as bupropion also can cause SIADH, although in our experience bupropion often may be a reasonable and relatively low-risk alternative to SSRIs or SNRIs. SIADH has been reported to occur anywhere from 2 days to many months after the initiation of a causal psychotropic agent; typically it occurs during the first few weeks of treatment with an antidepressant but may have a more variable time of onset during therapy with other psychotropic agents. Many nonpsychotropic agents also may cause hyponatremia or SIADH; these drugs include, among others, diuretics (e.g., amiloride and thiazide diuretics), antineoplastic drugs (e.g., vinca alkaloids), and the fibrate clofibrate.

The formal diagnosis of SIADH entails the presence of hypotonic hyponatremia plus lower serum osmolality (usually ~240–275 mOsm/kg) than urine osmolality (usually >100–200 mOsm/kg), as well as increased urine sodium (>30 mEq/L). Patients are typically euvolemic and have normal hepatic, renal, cardiac, thyroid, and adrenal function. (Importantly, hyponatremia with high serum osmolality points to other medical etiologies than SIADH, such as hyperglycemia or hyperosmolar hyperglycemic nonketotic coma.) Hyponatremia may manifest without symptoms or may involve nonspecific features such as weakness, lethargy, headache, and weight gain. Neuropsychiatric signs (e.g., confusion, seizures) may occur when serum sodium levels fall below ~120 mmol/L. The differential diagnosis of noniatrogenic hyponatremia is vast, as summarized in Table 10–1.

Laboratory assessment of hyponatremia includes measurement of urine electrolytes and osmolality. A diagnosis of SIADH is supported by concentrated urine (i.e., elevation of both urine Na⁺ [>20 mmol/L] and urine osmolality [>100 mmol/L]), whereas dilute urine (i.e., urine Na⁺ <20 mmol/L and urine osmolality <100 mmol/L) more likely suggests psychogenic polydipsia.

In mild euvolemic hyponatremia caused by psychotropic agents, elimination of the suspected causal agent in addition to fluid restriction to about 1 L/day is usually the preferred first-line intervention and often leads to resolution of the abnormality. This intervention may require at least temporarily withholding most classes of major psychotropic drugs or, if necessary, choosing an alternative pharmacotherapy that involves a novel mechanism from that of the suspected causal agent. Most authorities caution against rapid correction of low serum sodium levels (e.g., via aggressive infusion of hypertonic saline) because of the risk for inducing central pontine myelinolysis. Severe acute hyponatremia should be gradually corrected in a medical setting via intravenous infusion of sodium chloride solution, usually no faster than an initial rate of 1–2 mmol/L per hour.

The tetracycline antibiotic demeclocycline is sometimes used in the treatment of hyponatremia because of its ability to inhibit the renal effects of ADH. For instances in which continued therapy with a suspected causal psychotropic agent is deemed clinically necessary, adjunctive demeclocycline initially dosed at 900–1,200 mg/day may be advisable (Spigset and Hedenmalm 1995). Polyuria typically occurs within 1–2 weeks, and the dosage may then be gradually reduced, usually to 300–900 mg/day, in order to maintain normal serum sodium levels. Notably, lithium also inhibits the renal effects of ADH and is sometimes recommended as an alternative strategy in the management of hyponatremia.

In medical patients with SIADH who are taking an antidepressant, psychiatrists are often asked to render an opinion on the likelihood that the antidepressant is a causal factor, along with recommendations about continuing versus stopping an existing antidepressant and advice about the choice and timing of starting an alternative antidepressant. Generally speaking, one is obliged to stop existing antidepressants unless another known etiology exists. In the ideal, until serum sodium normalizes, one would not initiate another agent that could potentially also cause hyponatremia. However, in our experience, if ongoing antidepressant pharmacotherapy is indicated, it is reasonable to favor the initiation of either mirtazapine or bupropion, or sometimes a tricyclic or possibly a psychostimulant, when the risk–benefit ratio demands uninterrupted antidepressant therapy.

Metabolic Acidosis and Alkalosis