Lithium, an NSAID, and a Falling eGFR
Ms. R is a 62-year-old woman with bipolar I disorder, euthymic for six years on lithium carbonate ER 450 mg twice daily (serum level 0.85 mmol/L three months ago). Her eGFR was 68 mL/min/1.73 m² in March and is 46 today. She reports a coarse hand tremor, nocturia three times nightly, and new knee pain for which she began naproxen 500 mg twice daily three weeks ago. TSH is 7.4 mIU/L with normal free T4; calcium 10.6 mg/dL. Blood pressure 138/84. She has never had a manic episode while taking lithium and is frightened of relapse; she asks to 'just keep everything the same.'
1. What is the most likely driver of the eGFR decline, and how would you sequence evaluation and management over the next two weeks?
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Most likely driver: naproxen. NSAIDs reduce afferent arteriolar perfusion through prostaglandin inhibition and simultaneously increase proximal tubular lithium reabsorption, so the combination can raise creatinine and the lithium level together. The three-week timing fits.
Next two weeks:
- Stop naproxen today. Substitute topical diclofenac or acetaminophen and explicitly warn against OTC ibuprofen.
- Now: lithium level, basic metabolic panel, urinalysis, urine albumin-to-creatinine ratio, spot urine osmolality, calcium and PTH.
- Recheck creatinine, eGFR and lithium in 5-7 days; a reversible NSAID effect should show improvement.
- Encourage hydration; avoid dehydration, ACE inhibitors, thiazides and salt restriction.
- Nocturia plus a low osmolality would suggest lithium-related nephrogenic diabetes insipidus; calcium 10.6 requires PTH to screen for lithium-associated hyperparathyroidism.
If eGFR does not recover after the NSAID is withdrawn, the differential shifts toward lithium tubulointerstitial disease, and nephrology input is warranted. Document the interaction and counsel her explicitly, since she is likely to self-treat knee pain again.
2. Do you continue, reduce, or stop lithium, and how do you handle the thyroid finding?
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She is not toxic (level 0.85, no confusion, no vomiting), so this is a dose-adjustment problem rather than an emergency. Continuing lithium is defensible because she has six stable years and no clear contraindication, but the current dose is now excessive for an eGFR of 46.
- Reduce to 450 mg daily (or 300 mg twice daily), anticipating that stopping naproxen will also lower the level; recheck in 5-7 days and target roughly 0.5-0.7 mmol/L in an older adult with reduced clearance.
- Do not stop abruptly; abrupt discontinuation after long-term stability carries a substantial early relapse risk.
- TSH 7.4 with normal free T4 is subclinical hypothyroidism, common on lithium. Repeat in 4-6 weeks; if persistent, rising, or symptomatic, start levothyroxine 25-50 mcg daily. Treating it may also improve the tremor.
- Reassess the tremor: lithium level, thyroid, anxiety and benztropine or other co-prescriptions all contribute.
- Counsel on sick-day rules: hold lithium during vomiting, diarrhea or dehydration and call.
3. If lithium ultimately has to be discontinued, how would you choose and sequence a maintenance alternative?
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Taper lithium over at least four weeks rather than stopping abruptly, and choose the alternative based on her episode history and medical profile.
- Valproate is reasonable for manic-predominant illness but carries tremor, weight gain, hepatic and pancreatic risk, and needs level monitoring; her existing tremor makes it a less attractive first choice.
- Lamotrigine is weak for mania prevention and is a poor substitute if her history is manic-dominant.
- Atypical antipsychotic (quetiapine or aripiprazole) is a practical option; screen for metabolic syndrome, QT and orthostasis, and discuss the shift in side-effect burden.
- If renal function stabilizes on a lower lithium dose, continuing lithium with closer monitoring is often better than switching, given her sustained response.
Whichever route is taken, arrange monthly review for the first three months, a written relapse plan naming early warning signs, and involvement of her partner in monitoring sleep and spending. Document the shared decision, including her stated fear of relapse.