What are the adverse effects of lithium therapy and the recommended monitoring and management strategies?

Lithium Side Effects and Management

Common Side Effects

Lithium causes a range of common side effects including tremor, gastrointestinal symptoms, polyuria-polydipsia, and weight gain, along with serious organ-specific toxicities affecting the kidneys, thyroid, and parathyroid glands that require systematic monitoring. 1

Frequent Adverse Effects

• Gastrointestinal: Nausea, diarrhea, and abdominal discomfort occur commonly, particularly during treatment initiation 2, 1
• Neurological: Fine postural tremor affects 4-20% of patients and is exacerbated by caffeine and concomitant psychotropic medications 3
• Renal: Polyuria and polydipsia are typical complaints, with patients experiencing obligate polyuria and secondary thirst 2, 3
• Weight gain: Approximately 30% of patients gain 4-10 kg during long-term treatment 3, 4
• Dermatological: Exacerbation of psoriasis and edema may occur 3
• Cognitive: Memory impairment, reduced vigilance, and slowed reaction time are reported, though effects are typically mild 3

Organ-Specific Toxicities

Renal Effects

• Reduced urinary concentrating ability occurs in most patients, with glomerular filtration rate decreasing by an average of 6.22 mL/min 4
• Nephrogenic diabetes insipidus develops with long-term therapy, manifesting as polyuria up to 15% below normal maximum concentrating ability 4
• Approximately 20% of patients experience a decline in glomerular filtration rate, though progression to end-stage renal disease requiring dialysis is rare (0.5% of patients) 3, 4
• Women younger than 60 years are at highest risk for renal dysfunction 5

Thyroid Dysfunction

• Hypothyroidism is the most common endocrine complication, with lithium increasing risk 5.78-fold compared to placebo 4
• Thyroid-stimulating hormone increases by an average of 4.00 iU/mL during treatment 4
• Lithium inhibits thyroid hormone release and may induce goiter, with circulating thyroid auto-antibodies frequently present 3
• Thyrotoxicosis occurs less commonly but is a recognized complication 3
• Women are at greater risk than men for developing thyroid disorders 5

Parathyroid and Calcium Abnormalities

• Hyperparathyroidism and hypercalcemia are associated with long-term lithium use 3, 6
• Blood calcium increases by an average of 0.09 mmol/L 4
• Parathyroid hormone increases by 7.32 pg/mL on average 4
• Lithium treatment increases the risk of elevated total serum calcium by 1.43-fold 5

Lithium Toxicity

Risk Factors and Presentation

• Toxic levels are close to therapeutic levels, with toxicity risk beginning at 1.5 mEq/L and serious toxicity at >2.0 mEq/L 7, 1
• Early signs include tremor, nausea, diarrhea, polyuria-polydipsia, vomiting, mild ataxia, drowsiness, and muscular weakness 2, 1
• Severe toxicity presents with cardiovascular effects including arrhythmias, ECG alterations, hypotension, and myocardial dysfunction 2
• Neurological manifestations in severe cases include confusion, extrapyramidal symptoms, and potentially irreversible brain damage 1, 3

Precipitating Factors

• Dehydration, medication interactions (especially NSAIDs), and renal impairment are common precipitants 2, 7
• Protracted sweating, diarrhea, or intercurrent infection with fever decrease lithium tolerance 1
• Concomitant use of diuretics or ACE inhibitors reduces renal clearance and increases toxicity risk 1

Monitoring Requirements

Baseline Assessment

Before initiating lithium, obtain: complete blood count, thyroid function tests (TSH, free T4), renal function (BUN, creatinine, GFR), serum electrolytes including calcium, and urinalysis 8, 7

Ongoing Monitoring

• During acute phase: Check serum lithium concentrations twice weekly until stabilized 8, 7
• Maintenance phase: Monitor lithium levels, renal function, and thyroid function every 3-6 months 8
• Calcium levels should be checked regularly given the consistent finding of hyperparathyroidism 4
• More frequent monitoring is required for patients with GFR <60 mL/min/1.73 m² 7

Management Strategies

Prevention of Toxicity

• Temporarily suspend lithium during intercurrent illness, IV radiocontrast administration, bowel preparation, or prior to major surgery 2, 7
• Maintain adequate hydration (2500-3000 mL daily) and normal salt intake, especially during initial stabilization 1
• Avoid concomitant NSAIDs which significantly increase lithium levels and toxicity risk 2, 7, 1
• NSAIDs including COX-2 inhibitors can increase steady-state lithium levels by approximately 17% 1

Dose Adjustments for Renal Impairment

• For GFR <60 mL/min/1.73 m², use lower doses with more frequent monitoring 7
• Reduce dose by 50% in patients with GFR <30 mL/min/1.73 m² 7

Special Populations

• Elderly patients: Start with lower doses (150 mg/day) due to increased sensitivity and reduced clearance 7
• Pregnancy: Lithium is FDA Category D; avoid during first trimester unless maternal benefit exceeds fetal risk 1
• Nursing mothers: Lithium is excreted in breast milk; nursing should generally not be undertaken during therapy as neonatal kidneys are particularly sensitive 1
• Children under 12 years: Use is not recommended due to insufficient safety data 1

Treatment of Toxicity

• Mild toxicity: Reduce or temporarily discontinue lithium, resume at lower dose after 24-48 hours 1
• Severe toxicity: Hemodialysis is the treatment of choice for serum levels ≥3.5 mEq/L with significant symptoms, or any level with severe cardiovascular compromise 2
• Continue hemodialysis until level <1.0 mEq/L is achieved after redistribution (typically 6-8 hours, with measurement 4-6 hours post-dialysis to assess rebound) 2
• Supportive measures include gastric lavage, correction of fluid and electrolyte imbalance, and regulation of kidney function 1
• For arrhythmias, correct electrolytes (especially potassium and magnesium); avoid QT-prolonging antiarrhythmics if QT prolongation is present 2

Management of Specific Side Effects

• Hypothyroidism: Easily diagnosed and treated with supplemental thyroid hormone without necessarily discontinuing lithium 8, 3
• Tremor: Minimize by timing lithium dose appropriately and keeping levels at lower end of therapeutic range 9
• Weight gain: More difficult to manage and often contributes to nonadherence 9

Patient Education

Patients and families must be educated to recognize early signs of toxicity (diarrhea, vomiting, tremor, ataxia, drowsiness, muscular weakness) and discontinue lithium immediately while contacting their physician 8, 1

Patients should be cautioned that lithium may impair mental and physical abilities, requiring care with activities like operating vehicles or machinery 1