A 32-year-old woman with bipolar I disorder is stable on lithium carbonate. She presents with polyuria, polydipsia, and fine tremor. Her serum lithium is 0.9 mEq/L. Which mechanism best explains the polyuria in this setting?

• A Lithium causes direct glomerular toxicity leading to decreased GFR
• B Lithium induces hypothyroidism which reduces free water clearance
• C Lithium impairs the renal collecting duct response to antidiuretic hormone by downregulating aquaporin-2 channels ✓
• D Lithium causes syndrome of inappropriate ADH secretion

Explanation

Lithium-induced nephrogenic diabetes insipidus is the most common renal side effect of lithium. Lithium enters collecting duct principal cells via amiloride-sensitive channels and inhibits adenylyl cyclase, reducing cAMP-mediated insertion of aquaporin-2 water channels; the tubule becomes unresponsive to ADH, causing polyuria and compensatory polydipsia. Amiloride can be used to treat this condition by blocking lithium entry into principal cells.

Reference: Kaplan & Sadock's Synopsis of Psychiatry, 11th ed.

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