Lithium

• Bipolar Disorder
• Mania Treatment
• Mood Stabilization
• Treatment-Resistant Depression (augmentation)

Lithium is a mood stabilizer that has been the cornerstone of bipolar disorder treatment for decades. Despite its narrow therapeutic index, lithium remains a first-line treatment due to its proven efficacy in preventing manic and depressive episodes and its unique anti-suicidal effects.

Mechanism of Action

Lithium's precise mechanism of action in mood stabilization is not fully understood, but multiple effects have been identified. Lithium inhibits glycogen synthase kinase-3 (GSK-3), an enzyme involved in many cellular processes including mood regulation. It also reduces protein kinase C activity, modulates inositol monophosphatase (depleting inositol and reducing phosphatidylinositol signaling), and affects neurotransmitter systems including serotonin and norepinephrine. Lithium has neuroprotective effects, potentially increasing gray matter volume and promoting neurogenesis. It also affects circadian rhythms and gene expression through multiple pathways.

Available Formulations

Lithium is available as lithium carbonate capsules (150 mg, 300 mg, 600 mg), tablets (300 mg), extended-release tablets (300 mg, 450 mg), and lithium citrate oral solution (8 mEq/5 mL, equivalent to lithium carbonate 300 mg). Different formulations are not interchangeable on an mEq basis due to varying absorption. Serum lithium levels should be monitored when switching formulations.

Medical Uses

Lithium is FDA-approved for the treatment of manic episodes of bipolar disorder and maintenance treatment of bipolar disorder to prevent or diminish the intensity of subsequent episodes. It is also approved as an augmentation strategy for treatment-resistant depression. Lithium is considered first-line therapy for bipolar disorder due to extensive evidence of efficacy and unique anti-suicidal properties.

Dosing Guidelines

Dosing is individualized based on serum lithium levels and clinical response. For acute mania, starting dose is typically 300-600 mg two to three times daily, with dose adjustment to achieve serum levels of 0.8-1.2 mEq/L. For maintenance therapy, target levels are typically 0.6-1.0 mEq/L. Extended-release formulations allow twice-daily dosing. Serum lithium levels should be measured 12 hours post-dose (trough level). Regular monitoring of lithium levels, renal function, and thyroid function is essential.

Important Safety Information

Lithium has a narrow therapeutic index; toxicity can be fatal. Lithium toxicity can occur at therapeutic doses if sodium or fluid balance is disrupted. Signs of toxicity include tremor, ataxia, diarrhea, vomiting, drowsiness, and in severe cases, seizures, cardiac arrhythmias, and permanent neurological damage. The medication is contraindicated in patients with significant renal or cardiovascular disease. Long-term use can cause hypothyroidism, nephrogenic diabetes insipidus, and chronic kidney disease. Regular monitoring of lithium levels, renal function (creatinine, eGFR), and thyroid function (TSH) is required.

Drug Interactions

NSAIDs, ACE inhibitors, ARBs, and diuretics (especially thiazides) can increase lithium levels and toxicity risk. Sodium depletion (low-salt diet, dehydration) increases lithium retention. Caffeine and theophylline increase lithium excretion. Metronidazole may increase lithium levels. Some antipsychotics may enhance neurotoxic effects. Medications affecting renal function require careful monitoring.

Special Populations

Lithium is associated with an increased risk of Ebstein's anomaly and other cardiac malformations when taken during the first trimester of pregnancy. Use during pregnancy requires careful risk-benefit assessment. Lithium is excreted in breast milk at 30-50% of serum concentrations; breastfeeding is generally discouraged. Safety and efficacy have been established in pediatric patients 7 years and older for bipolar disorder. Elderly patients may require lower doses due to reduced renal function; closer monitoring is needed. Dose reduction is required in renal impairment; lithium is contraindicated in severe renal impairment.