Lithium is a gold-standard treatment for bipolar disorder (BD) in older adults. It treats both the manic and depressive phases, and prevents relapse, while also reducing suicide risk and psychiatric hospitalizations (Rej S et al, Drugs Aging 2015;32(1):31–42). Data also suggest lithium has neuroprotective properties that may reduce the risk of dementia, stroke, cancer, and diabetes (Shulman KI et al, Bipolar Disord 2019;21(2):117–123). As a bonus, older adults report positive attitudes regarding their treatment with lithium.

Even with all its benefits, many are hesitant to prescribe lithium in older adults due to concerns about side effects and toxicity. However, with cautious use and monitoring, lithium can be an important treatment for older adults with BD.

Dosing in older adults

Due to their reduced renal clearance and reduced volume of distribution, use lower doses in older adults (about 30%–50% of the dose you would use in younger adults). The International Society for Bipolar Disorders Task Force recommends a target serum level of 0.4–0.8 mEq/L (Fotso S et al, Drugs Aging 2019;36(2):147–154). Dose once daily at bedtime to avoid daytime somnolence and renal problems.

Monitoring lithium

• Check lithium levels five or six days after starting 
• Also check lithium levels after adjusting the dose or adding medications that interact with lithium
• Monitor serum lithium levels every three to six months
• Monitor estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), serum creatinine (SCr), and electrolytes at baseline and every three to six months; be on the lookout for renal toxicity
• Monitor thyroid-stimulating hormone (TSH), calcium, and parathyroid hormone (PTH) levels at baseline and every six to 12 months
• Monitor ECG at baseline and periodically (based on comorbidities), every six to 12 months
• Assess the patient’s gait, tremor, and cognition at every visit

See “Minimizing Adverse Effects of Lithium in Older Adults” table  for current monitoring recommendations. 

Adverse renal effects

Lithium is notorious for its effects on the kidneys, most notably nephrogenic diabetes insipidus (NDI) and chronic kidney disease (CKD). Ask your patients whether they experience excessive thirst or frequent urination.

Nephrogenic diabetes insipidus

In NDI, the kidneys have a decreased ability to concentrate urine. Lithium inhibits antidiuretic hormone (ADH) and therefore reduces the reabsorption of water. Older adults are at highest risk of developing NDI, particularly those taking lithium at higher doses, more frequently than once daily, or for longer durations—generally, longer than 10 years is associated with greater decline in kidney function (Fransson F et al, Lancet Psychiatry 2022;9(10):804–814). It’s important to monitor for NDI because it increases a patient’s risk of developing hypernatremia, lithium toxicity, and CKD (Rej et al, 2015).

NDI presents with excessive thirst, increased urination (large volumes of urine several times a day), and dehydration. To rule out other conditions, such as diabetes or diuretic use, check hemoglobin A1c (HbA1c) and electrolytes, and ask about current medications. If you suspect NDI, liaise with the patient’s primary care clinician. A 24-hour urine collection test (a urine volume greater than 3000 mL/day is indicative of NDI) or a urinalysis (test for low urine-specific gravity, which is a marker for NDI) can support the diagnosis (Gitlin M and Bauer M, Int J Bipolar Disord 2023;11(1):35).

Chronic kidney disease

CKD is defined as a decrease in kidney function, typically an eGFR of less than 60 mL/min for at least three months. Kidney damage is more likely to occur with lithium when patients have a baseline eGFR less than 60 mL/min. 

Other risk factors for developing or worsening CKD with lithium include: 

• Concurrent medications that increase lithium levels 
• Dehydration
• Diabetes
• Higher doses (resulting in serum levels greater than 0.8 mEq/L)
• Long-term lithium use (most pronounced after 10 years) 
• Greater than once-daily dosing
• Previous episodes of NDI or acute kidney injury (AKI) 

In patients at risk, monitor eGFR more frequently (every three to six months), decrease lithium dose and/or frequency (rarely, you may consider every-­other-day dosing), and use an immediate-­release formulation. Encourage patients on lithium to drink plenty of water. If kidney function is not actively worsening, patients can remain on lithium even with CKD (Gitlin and Bauer, 2023).

Consider a nephrology consultation for older adults if:

• Baseline eGFR <60 mL/min
• Decline in eGFR ≥5 mL/min in one year or ≥10 mL/min in five years

Data suggest that higher lithium serum levels and longer duration of treatment (perhaps related to poor monitoring rather than lithium itself) lead to the increased risk of CKD (Rej et al, 2015). For the majority of older adults taking lithium, staying at lower doses and closely monitoring target levels of less than 0.8 mEq/L minimizes this risk. End-stage renal disease in older adults taking lithium is relatively uncommon (0.5%–2%) and typically related to very high lithium levels (Rej et al, 2015).

Other adverse effects

Neurological

Consider neurotoxicity in patients with a coarse tremor, altered mental status (confusion or cognitive dulling), muscle twitching, or gait changes. Risk increases with higher lithium levels, more frequent dosing, dehydration, AKI, or drug interactions. Lithium neurotoxicity can be chronic and may be associated with normal serum levels; look out for it in older adults taking lithium for many years.

Monitor neurologic function at every visit, and ask patients and caregivers to keep an eye out for these symptoms. If you’re concerned about neurologic effects, try to reduce the lithium dose and avoid medications that raise lithium levels. Attempt to minimize other medications with neurotoxic effects (eg, benzodiazepines, hypnotics, anticonvulsants, opioids). 

Endocrine 

Lithium is associated with hypothyroidism, hypercalcemia, and hyperparathyroidism. Hypothyroidism is common among older adults taking lithium; risk factors include: 

• Iodine deficiency
• Cigarette smoking
• Presence of thyroid antibodies
• Female sex
• Diabetes 

(Source: Dols A and Beekman A, Clin Geriatr Med 2020;36(2):281–296)

Patients who develop hypothyroidism are usually diagnosed during the first years of lithium treatment and should be treated with levothyroxine. Ask about weight gain, lethargy, dry skin, and cold intolerance.

Cardiac

Lithium inhibits voltage-gated sodium channels, which causes a decrease in intracellular potassium and leads to ECG changes that resemble hypokalemia when serum potassium levels are normal (Mehta N and Vannozzi R, Clin Cardiol 2017;40(12):1363–1367). T-wave abnormalities and sinus node dysfunction are common ECG findings in patients with therapeutic levels of lithium and are usually benign and asymptomatic. QT interval prolongation, potentially leading to torsades de pointes and fatal arrhythmias, is rare and typically occurs in patients with lithium serum levels greater than 1.5 mEq/L. Toxic levels are also associated with sinoatrial block, intraventricular conduction delay, ST depression/elevation, the Brugada pattern (in patients with genetic predisposition), atrioventricular conduction delay, and changes in the QT dispersion ratio. 

There are no standard guidelines on ECG monitoring, but a safe approach is to obtain a baseline ECG and repeat it periodically (every six to 12 months), with the frequency depending on the severity of the patient’s comorbidities. Think about more frequent monitoring in patients with kidney disease. Additionally, monitor blood pressure and pulse, and pay attention to edema.

Drug interactions

Medications that lower kidney perfusion and/or increase lithium levels can increase a patient’s risk of CKD, neurotoxicity, and cardiac toxicity. These ­include: 

• Angiotensin-converting enzyme inhibitors (ACEIs)
• Angiotensin receptor blockers (ARBs) 
• Diuretics (especially thiazides)
• Nonsteroidal anti-inflammatory ­medications (NSAIDs) 

If the patient has to take one of these medications, monitor lithium levels more closely and adjust dosing to a serum level less than 0.8 mEq/L. Remember the potential for additive neurotoxic effects with benzodiazepines, hypnotics, opioids, and ­anticonvulsants.

Carlat Verdict

Lithium is very effective in BD, although under-prescribed in older adults. To minimize long-term adverse effects, prescribe it once nightly and monitor patients regularly.