What alternative medications can cause Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) in patients, particularly the elderly or those with a history of malignancies, neurological disorders, or psychiatric conditions?

Alternative Medications Causing SIADH

The most common alternative medications causing SIADH include SSRIs (particularly sertraline and citalopram), SNRIs (venlafaxine), carbamazepine, oxcarbazepine, NSAIDs, tramadol, and certain antipsychotics. 1, 2

High-Risk Medication Classes

Antidepressants

• SSRIs are strongly associated with SIADH, with moderate to high level evidence demonstrating this relationship 3
• Sertraline specifically causes hyponatremia through SIADH mechanism, with cases documented showing serum sodium lower than 110 mmol/L 4
• Citalopram has been documented to cause SIADH in elderly patients, with symptoms resolving after discontinuation 5
• SNRIs (particularly venlafaxine) carry similar risk to SSRIs, with documented cases of SIADH occurring in the same patient sequentially with both drug classes 5, 3
• The risk of SIADH with antidepressants is highest during the first weeks of treatment 6

Anticonvulsants

• Carbamazepine and oxcarbazepine have moderate to high level evidence for causing SIADH 3
• These medications were specifically added to the 2019 AGS Beers Criteria list of drugs associated with hyponatremia or SIADH 1

Analgesics

• Tramadol was added to the list of drugs associated with hyponatremia or SIADH in the 2019 AGS Beers Criteria update 1
• NSAIDs (both nonselective and COX-2 inhibitors) can induce SIADH, particularly when combined with other offending agents 7, 8
• Naproxen combined with SSRIs represents a particularly dangerous combination that can precipitate acute-on-chronic hyponatremia 7

Antipsychotics

• Antipsychotics have moderate to high level evidence demonstrating association with SIADH 3
• The risk with antipsychotics appears more spread out over time compared to antidepressants, rather than concentrated in the initial treatment period 6

Chemotherapeutic Agents

• Cisplatin, vinca alkaloids (vincristine, vinblastine), cyclophosphamide, and carboplatin can induce SIADH 2
• Note: The 2019 AGS Beers Criteria removed carboplatin, cyclophosphamide, cisplatin, and vincristine from their SIADH list because prescribing of these highly specialized drugs fell outside the scope of general geriatric criteria 1

High-Risk Patient Populations

Elderly Patients

• Elderly patients are at greater risk of developing hyponatremia with SSRIs and SNRIs 4
• Aging is associated with increased sensitivity to hyponatremia due to age-related reduction of glomerular filtration rate 1
• Elderly patients have enhanced ADH release as a compensatory mechanism, increasing vulnerability to drug-induced SIADH 9

Patients on Diuretics

• Patients taking diuretics or who are otherwise volume depleted are at greater risk for SIADH 4
• The combination of thiazide diuretics with SSRIs or other SIADH-inducing medications substantially increases risk 8

Patients with Multiple Medications

• The use of SIADH-inducing drugs in combination dramatically increases risk 8
• Advanced age combined with multiple drug therapies represents the highest risk scenario 5

Critical Clinical Pitfalls

Combination Therapy Risks

• Avoid combining SSRIs/SNRIs with NSAIDs, as this represents a particularly dangerous combination 7
• The concurrent use of multiple CNS agents (antidepressants, antipsychotics, benzodiazepines, antiepileptics, opioids) increases fall risk and may compound SIADH risk 1

Monitoring Requirements

• Sodium levels should be monitored during the first weeks of SSRI/SNRI treatment, when risk is highest 6, 5
• For patients with risk factors (age >65, diuretic use, multiple medications), baseline and serial sodium monitoring is warranted 3

Medication Reconciliation

• Careful medication reconciliation must be performed to identify all potential SIADH-inducing agents 7
• Discontinuation of the offending medication is essential in treating drug-induced SIADH 2, 8

Management Algorithm

When SIADH is Suspected

• Discontinue the offending psychotropic or NSAID immediately if symptomatic hyponatremia is present 2
• Implement fluid restriction to 1 L/day for mild to moderate cases 2, 4
• For severe symptomatic hyponatremia (sodium <120 mEq/L with neurological symptoms), administer 3% hypertonic saline with target correction of 6 mmol/L over 6 hours, maximum 8 mmol/L in 24 hours 2

Medication Substitution Strategy

• If continued antidepressant treatment is needed, substitute with a medication less likely to cause SIADH 6, 3
• Consider switching to a different pharmacological class rather than rechallenging with the same mechanism of action 7
• Monitor serum sodium closely during any medication transition 5, 3

Special Considerations

• Demeclocycline can be considered as second-line treatment for chronic SIADH if the offending medication must be continued 2, 6
• Evaluate for other contributing factors including excessive fluid intake, smoking, and underlying psychiatric conditions that may cause psychogenic polydipsia 6