Lithium - Drug Monograph

Introduction

Lithium is a mood-stabilizing medication that has been used clinically since 1949 for the treatment of bipolar disorder. As a first-line treatment for acute mania and maintenance therapy in bipolar disorder, lithium remains one of the most effective psychotropic medications available. It is classified as an antimanic agent and is the gold standard against which other mood stabilizers are measured.

Mechanism of Action

Lithium's exact mechanism of action remains incompletely understood, but several neurobiological effects have been identified:

• Second messenger systems: Modulates inositol monophosphatase and glycogen synthase kinase-3 (GSK-3) pathways
• Neurotransmitter systems: Enhances serotonin transmission and reduces norepinephrine activity
• Neuroprotective effects: Increases brain-derived neurotrophic factor (BDNF) and promotes neuronal growth
• Ion transport: Alters sodium transport in nerve and muscle cells
• Circadian rhythm regulation: Stabilizes biological rhythms disrupted in mood disorders

Indications

• Treatment of manic episodes of bipolar disorder
• Maintenance treatment for bipolar disorder to prevent or diminish the intensity of subsequent episodes

• Augmentation therapy for treatment-resistant depression
• Schizoaffective disorder
• Cluster headaches
• Impulse control disorders

Dosage and Administration

• Lithium carbonate: Immediate-release tablets (300 mg), controlled-release tablets (450 mg)
• Lithium citrate: Liquid formulation (8 mEq/5 mL)

• Initial therapy: 600-900 mg/day in divided doses
• Maintenance therapy: 900-1200 mg/day
• Target serum levels:

- Acute mania: 0.8-1.2 mEq/L - Maintenance: 0.6-0.8 mEq/L - Geriatric patients: 0.4-0.7 mEq/L

• Elderly: Reduced dosing due to decreased renal function
• Renal impairment: Dose reduction and more frequent monitoring required
• Pediatric: Limited data; use with extreme caution

Pharmacokinetics

• Absorption: Rapid and complete from GI tract; food may delay but not reduce absorption
• Distribution: Widely distributed throughout body water; no protein binding
• Metabolism: Not metabolized; excreted unchanged
• Elimination: Primarily renal excretion (95%); half-life 18-36 hours
• Steady-state: Reached in 5-7 days with regular dosing

Contraindications

• Severe renal impairment (CrCl <30 mL/min)
• Significant cardiovascular disease
• Severe dehydration or sodium depletion
• Addison's disease
• Pregnancy (first trimester relative contraindication)
• Known hypersensitivity to lithium

Warnings and Precautions

• Lithium toxicity is closely related to serum lithium levels and can occur at therapeutic doses

• Renal effects: May cause nephrogenic diabetes insipidus and chronic interstitial nephritis
• Thyroid effects: Can cause hypothyroidism and goiter
• Cardiac effects: May cause T-wave flattening or inversion
• Teratogenicity: Associated with cardiac malformations (Ebstein's anomaly)
• Dehydration risk: Patients must maintain adequate fluid and salt intake
• Elderly patients: Increased risk of toxicity and adverse effects

Drug Interactions

• Diuretics (especially thiazides): Increase lithium reabsorption → toxicity risk
• NSAIDs: Reduce renal clearance → increased lithium levels
• ACE inhibitors/ARBs: May increase lithium levels
• Metronidazole: Case reports of lithium toxicity
• Theophylline: May decrease lithium levels
• Serotonergic drugs: Increased risk of serotonin syndrome

Adverse Effects

• Fine hand tremor
• Polyuria, polydipsia
• Nausea, diarrhea
• Weight gain
• Mild cognitive impairment

• Lithium toxicity (levels >1.5 mEq/L)
• Nephrogenic diabetes insipidus
• Hypothyroidism
• Renal impairment
• Cardiac arrhythmias
• Seizures
• Serotonin syndrome

• Mild: 1.5-2.5 mEq/L (nausea, tremor, drowsiness)
• Moderate: 2.5-3.5 mEq/L (confusion, agitation, ECG changes)
• Severe: >3.5 mEq/L (seizures, coma, cardiovascular collapse)

Monitoring Parameters

• Serum lithium levels: 12 hours post-dose, initially weekly, then every 2-3 months when stable
• Renal function: Serum creatinine, BUN at baseline and every 3-6 months
• Thyroid function: TSH at baseline and every 6-12 months
• Electrolytes: Sodium levels regularly
• ECG: Baseline and as clinically indicated
• Pregnancy test: In women of childbearing potential

• Draw levels 12 hours after last dose
• Maintain consistent salt and fluid intake before testing
• Monitor more frequently during illness, dehydration, or medication changes

Patient Education

• Take lithium exactly as prescribed at the same times each day
• Maintain consistent fluid intake (2-3 L/day) and salt intake
• Recognize early signs of toxicity: nausea, vomiting, diarrhea, drowsiness, tremor, confusion
• Regular blood tests are essential for safety
• Report any illness, especially with vomiting or diarrhea
• Avoid dehydration during exercise or hot weather
• Use effective contraception; discuss pregnancy plans with provider
• Do not make any medication changes without consulting prescriber
• Carry lithium identification card

• Limit caffeine and alcohol intake
• Maintain regular sleep patterns
• Report significant weight changes
• Inform all healthcare providers about lithium use

References

1. Goodwin GM, et al. Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2016;30(6):495-553.

2. Yatham LN, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170.

3. McKnight RF, et al. Lithium toxicity profile: a systematic review and meta-analysis. Lancet. 2012;379(9817):721-728.

4. Gitlin M. Lithium side effects and toxicity: prevalence and management strategies. Int J Bipolar Disord. 2016;4(1):27.

5. FDA Prescribing Information: Lithium Carbonate Tablets. Revised 2021.

6. Malhi GS, et al. The Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust N Z J Psychiatry. 2021;55(1):7-117.

7. Grandjean EM, Aubry JM. Lithium: updated human knowledge using an evidence-based approach. Part II: Clinical pharmacology and therapeutic monitoring. CNS Drugs. 2009;23(4):331-349.