Lithium Carbonate

Approved Indications:

• Acute Mania (Bipolar I Disorder):
  • Treatment of acute manic episodes in adults with bipolar disorder.
  • Controls symptoms such as hyperactivity, reduced need for sleep, and elevated mood.
• Maintenance Treatment of Bipolar Disorder:
  • Long-term maintenance therapy to prevent recurrence of manic and depressive episodes.
  • Reduces frequency and severity of mood swings.
• Schizoaffective Disorder (Adjunctive):
  • Used as adjunctive therapy in mood-related components of schizoaffective disorder to stabilize mood and behavior.

Clinically Accepted Off-label Uses:

• Cluster Headache Prophylaxis:
  • Used as a second-line agent in the prevention of chronic cluster headaches.
• Augmentation in Major Depressive Disorder (MDD):
  • Augments antidepressants in patients with treatment-resistant depression.
• Self-Injurious Behavior in Autism Spectrum Disorders:
  • May help reduce impulsivity and aggression in specific pediatric populations under close monitoring.

Route: Oral
Formulations: Immediate-release tablets, extended-release tablets, oral capsules, oral solution
Therapeutic Serum Level Targets:

• Acute Mania: 0.8–1.5 mEq/L
• Maintenance: 0.6–1.2 mEq/L
• Elderly: 0.4–0.8 mEq/L

Adults:

• Acute Mania:
  • Initial: 600 mg two to three times daily (immediate-release)
  • Titrate by 300–600 mg/day every 3–5 days based on serum levels and response
  • Maximum dose: ~2,400 mg/day
• Maintenance Therapy:
  • Usual: 900–1,200 mg/day in divided doses
  • Adjust to maintain serum levels between 0.6–1.2 mEq/L

Elderly Patients:

• Initial Dose: 150–300 mg twice daily
• Use lower targets and slower titration
• Monitor renal function and serum lithium levels frequently

Pediatric Use (≥7 years, off-label):

• Initial: 15–20 mg/kg/day in divided doses
• Titrate slowly with careful monitoring of serum levels and renal function
• Safety and efficacy must be individualized and specialist-guided

Renal Impairment:

• Mild to Moderate (CrCl 30–89 mL/min):
  • Start at reduced dose (by 25–50%)
  • Adjust according to serum levels and renal function
• Severe Renal Impairment (CrCl <30 mL/min):
  • Generally contraindicated unless no alternatives exist

Hepatic Impairment:
• No dose adjustment needed, but monitor fluid and electrolyte status

Serum Monitoring:
• Check 12-hour trough serum lithium level 5 days after dose change
• Recheck every 1–3 months during maintenance
• More frequent testing in elderly or with renal concerns

Lithium carbonate acts through multiple cellular mechanisms to stabilize mood. Its primary effect is the inhibition of inositol monophosphatase, which disrupts the phosphatidylinositol signaling cascade. This leads to decreased activity of second messengers involved in neurotransmitter signaling (e.g., serotonin, norepinephrine, dopamine, and glutamate). Lithium also modulates the activity of glycogen synthase kinase-3 beta (GSK-3β), influencing gene transcription, neuroplasticity, circadian rhythm regulation, and neuronal resilience. These cellular effects help reduce manic behavior and stabilize mood over the long term.

• Absorption: Nearly 100% oral bioavailability
• Onset of Action: 5–7 days (clinical effect)
• Peak Plasma Time:
  – Immediate-release: 1–3 hours
  – Extended-release: 4–8 hours
• Distribution: Volume of distribution: 0.6–0.9 L/kg; crosses blood-brain barrier slowly
• Protein Binding: None
• Metabolism: Not metabolized
• Half-life:
  – Adults: 18–36 hours
  – Elderly or renal impairment: May extend to 48–72 hours
• Excretion: ~95% excreted unchanged in urine
• Dialyzable: Yes; lithium is efficiently removed by hemodialysis

• Pregnancy:
  • FDA Category D
  • Increased risk of congenital malformations, especially Ebstein’s anomaly (a cardiac defect).
  • Avoid in the first trimester if possible; use only when benefits outweigh risks.
• Lactation:
  • Lithium is excreted into breast milk at levels approximating 30–50% of maternal serum.
  • Reports of infant toxicity (e.g., lethargy, hypotonia, ECG changes).
  • Breastfeeding is generally not recommended during lithium treatment.

• Primary Class: Mood Stabilizer
• Subclass: Antimanic Agent / Monovalent Cation

• Hypersensitivity to lithium or its components
• Severe renal impairment
• Clinically significant cardiovascular disease (e.g., arrhythmias, sick sinus syndrome)
• Severe dehydration or sodium depletion
• Use with thiazide diuretics, NSAIDs, or ACE inhibitors without close monitoring
• Pregnancy (especially first trimester, unless necessary)

• Narrow Therapeutic Index: Toxicity can occur with small increases in serum concentration
• Lithium Toxicity:
  – Early signs: Tremor, nausea, vomiting, diarrhea
  – Late signs: Ataxia, confusion, seizures, coma
• Renal Function: Monitor regularly; risk of chronic kidney disease with long-term use
• Thyroid Dysfunction: Risk of hypothyroidism and goiter; monitor TSH levels
• Fluid & Electrolyte Balance: Dehydration and sodium loss can raise lithium levels; maintain stable intake
• Cardiac Monitoring: Use cautiously in patients with conduction abnormalities or bradycardia
• Serotonin Syndrome: Risk increased with concurrent serotonergic drugs (SSRIs, MAOIs, TCAs)
• Do Not Discontinue Abruptly: May trigger relapse of mood symptoms

Common Side Effects:

• Neurologic: Fine tremor, headache, lethargy, cognitive slowing
• Gastrointestinal: Nausea, diarrhea, metallic taste
• Renal: Polyuria, polydipsia, nephrogenic diabetes insipidus
• Endocrine/Metabolic: Hypothyroidism, weight gain
• Dermatologic: Acne, psoriasis flare
• General: Edema, thirst

Serious or Rare Side Effects:

• Toxicity (Levels >1.5 mEq/L): Seizures, confusion, coma
• Chronic Kidney Disease (long-term use)
• Cardiac: ECG changes, arrhythmias
• Endocrine: Hyperparathyroidism, hypercalcemia
• Neurologic: Encephalopathy, irreversible neurologic damage (rare)

• Diuretics (Thiazides, Loops): Decrease lithium clearance → risk of toxicity
• NSAIDs (e.g., ibuprofen, naproxen): Decrease renal clearance → increased lithium levels
• ACE Inhibitors / ARBs: May raise lithium concentrations → monitor serum levels closely
• Sodium-Depleting Agents: Increase lithium reabsorption → risk of toxicity
• SSRIs / MAOIs / TCAs: Risk of serotonin syndrome
• Caffeine / Theophylline: May decrease lithium levels
• Antipsychotics (e.g., haloperidol): Risk of neurotoxicity and encephalopathy
• CYP450: No interaction – lithium is not metabolized by cytochrome enzymes

• Bipolar Disorder Guidelines (APA, NICE, CANMAT 2023): Lithium remains the first-line agent for acute mania and maintenance in bipolar I disorder.
• Suicide Prevention Data: Lithium significantly reduces the risk of suicide and self-harm in mood disorders; highlighted in recent meta-analyses.
• Renal Risk Recognition: Monitoring protocols increasingly emphasize renal surveillance due to risk of nephropathy from long-term use.

• Storage Temperature: 20°C to 25°C (68°F to 77°F)
• Permitted Excursions: Between 15°C and 30°C
• Humidity Protection: Store in a dry place, tightly closed container
• Light Protection: No special light precautions required
• Oral Solution: Shake well before use; follow manufacturer’s guidance
• Refrigeration: Not required