A 38-year-old woman with major depressive disorder is started on an antidepressant. After 3 weeks of therapy, she develops hyponatraemia (Na⁺ 128 mEq/L), confusion, and lethargy. Which of the following antidepressants is the MOST COMMON cause of this adverse effect?

## Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) with Antidepressants **Key Point:** SSRIs are the MOST COMMON antidepressant class causing hyponatraemia via SIADH, particularly in the first 2–4 weeks of therapy or after dose escalation. ### Mechanism of SIADH with SSRIs 1. Increased serotonergic tone in the hypothalamus 2. Enhanced ADH (vasopressin) secretion 3. Increased renal water reabsorption → hyponatraemia 4. Risk highest in elderly patients, females, and those on concurrent diuretics ### Comparative Risk Across Antidepressant Classes | Antidepressant Class | SIADH Risk | Mechanism | Clinical Notes | |---|---|---|---| | **SSRIs** | **Very High** | Direct serotonergic stimulation of ADH neurons | Most common; citalopram > fluoxetine > sertraline | | SNRIs | High | Less than SSRIs; noradrenaline may partially offset | Venlafaxine, duloxetine also implicated | | TCAs | Low–Moderate | Anticholinergic effects may reduce ADH; variable | | MAOIs | Low | Sympathomimetic effects; less ADH stimulation | Rarely reported | **High-Yield:** Citalopram and fluoxetine carry the highest SIADH risk among SSRIs. Sertraline and paroxetine have lower risk. ### Clinical Presentation - Onset: typically 1–4 weeks after initiation or dose increase - Symptoms: confusion, lethargy, headache, nausea, seizures (severe) - Lab: low serum Na⁺, low serum osmolality, inappropriately high urine osmolality - Urine sodium usually elevated (>40 mEq/L) ### Management 1. **Acute:** fluid restriction (500–1000 mL/day), hypertonic saline if symptomatic/severe 2. **Chronic:** switch to antidepressant with lower SIADH risk (e.g., mirtazapine, bupropion) or continue SSRI with monitoring 3. **Prevention:** baseline Na⁺ check, repeat at 1–2 weeks, educate on fluid intake **Clinical Pearl:** Elderly patients (>65 years) are at 3–5× higher risk of SSRI-induced hyponatraemia. Always check baseline sodium and recheck at 1–2 weeks in this population. **Warning:** Do NOT confuse SIADH with nephrogenic diabetes insipidus (lithium-induced) — in SIADH, urine osmolality is high; in nephrogenic DI, it is low.