Can lithium cause leukocytosis (elevated white blood cell count) in patients with a history of mood disorders?

Lithium-Induced Leukocytosis

Yes, lithium consistently causes leukocytosis (elevated white blood cell count) in the majority of patients, with increases typically appearing within the first few weeks of therapy and persisting throughout long-term treatment. 1, 2, 3

Mechanism and Characteristics of Lithium-Induced Leukocytosis

Lithium causes a true increase in total body neutrophils through increased production, not just redistribution. 4 The drug stimulates hematopoietic stem cells and increases production of colony-stimulating factor (CSF), which drives granulocyte production. 5, 4

Typical Pattern of WBC Elevation

• The mean increase in WBC count is approximately 2,237 cells/mm³ above baseline values, with most patients showing significant elevation (p < 0.001). 2
• Patients on lithium therapy typically demonstrate WBC counts averaging 11,950 ± 4,028 cells/mm³, which exceeds normal reference ranges. 2
• The leukocytosis appears within the first few weeks of treatment and persists throughout the entire course of therapy, remaining elevated for at least 1-2 years of continuous use. 3, 6

Specific Cell Types Affected

• Neutrophils, eosinophils, and possibly monocytes are routinely increased during therapeutic lithium exposure. 4
• Platelets tend to increase, while lymphocytes and erythrocytes remain unaffected. 4
• The FDA label notes that transient leukocytosis is among the miscellaneous reactions unrelated to dosage. 1

Relationship to Lithium Dose and Serum Levels

The leukocytosis is drug-related but does NOT appear to be dose-dependent or correlated with serum lithium concentrations. 2 However, one study found a significant correlation between lithium dose (not serum level) and degree of leukocytosis. 6 This suggests that some patients may achieve leukocyte elevation with lower-than-conventional doses, which has implications for using lithium therapeutically to treat leukopenic conditions. 6

Clinical Significance and Monitoring

When to Investigate Further

Leukocytosis from lithium is benign and expected, but clinicians should differentiate it from pathological causes. The FDA label provides specific guidance: 1

• If the WBC has dropped 3,000/mm³ over 1-3 weeks, or if immature cell forms are present, repeat the count immediately. 7
• If WBC remains between 3,000-3,500/mm³ and absolute neutrophil count (ANC) is >1,500/mm³, monitor with differential biweekly until WBC exceeds 3,500/mm³. 7
• If counts drop below 3,000/mm³ or ANC falls below 1,500/mm³, follow established neutropenia protocols. 7

Therapeutic Applications

Lithium has been used clinically to treat granulocytopenia resulting from radiation and chemotherapy, to boost immunoglobulins after vaccination, and to enhance natural killer cell activity. 5 The persistent elevation of leukocytes during long-term therapy suggests lithium might play a role in long-term management of certain leukopenic conditions using lower-than-conventional doses. 3, 6

Important Caveats

Lithium enhances immunological activities of monocytes and lymphocytes while causing granulocytosis and lymphopenia, demonstrating complex effects on different immune cell populations. 5

Neutrophil function generally remains unaffected by lithium, so the elevated WBC count represents increased quantity rather than altered cellular activity. 4

The leukocytosis is not always a consistent finding in all patients on long-term lithium therapy, though it occurs in the majority. 6 Baseline WBC counts should be established before initiating lithium to properly interpret subsequent elevations. 3, 6