Lithium

Generic Name: Lithium (as lithium carbonate or lithium citrate)
Drug Class: Mood stabilizer
Pharmacological Class: Monovalent cation (Li⁺), antimanic agent
ATC Code: N05AN01
Regulatory Status: Prescription-only medicine (Rx); narrow therapeutic index drug
Common Brand Names: Priadel, Camcolit, Lithobid, Eskalith, Lithonate, Quilonum

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Mechanism of Action

Lithium’s precise mechanism is not fully understood, but it is believed to act through multiple central nervous system pathways to stabilize mood. Key actions include:

1. Modulation of neurotransmitters:

   • Inhibits dopamine and glutamate (excitatory pathways)

   • Enhances GABA (inhibitory) function

2. Second messenger systems:

   • Inhibits inositol monophosphatase and glycogen synthase kinase-3β (GSK-3β)

   • Affects the phosphatidylinositol (PI) cycle involved in mood regulation

3. Neuroprotective and neuroplastic effects:

   • Promotes brain-derived neurotrophic factor (BDNF)

   • Enhances gray matter volume in key brain regions

Lithium is not a sedative or antipsychotic, but uniquely prevents mood swings and recurrence of manic/depressive episodes.

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Therapeutic Indications

1. Bipolar Disorder (manic-depressive illness):

   • Treatment and prevention of mania and hypomania

   • Maintenance therapy to reduce frequency and severity of mood episodes

   • Effective in preventing both manic and depressive relapses

2. Unipolar Major Depression (augmentation):

   • Used in treatment-resistant depression as augmentation with antidepressants

3. Acute Mania:

   • Reduces agitation, euphoria, insomnia, and grandiosity

4. Schizoaffective Disorder (off-label):

   • Adjunct for mood stabilization in psychosis with bipolar features

5. Suicide Prevention:

   • Long-term lithium use is associated with reduced suicidal behavior and mortality in bipolar patients

6. Cluster Headaches (off-label):

   • May be used as a prophylactic treatment for chronic cluster headaches

7. Neutropenia or leukopenia (off-label):

   • Occasionally used to increase neutrophil count in chemotherapy-related neutropenia

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Formulations and Strengths

• Lithium carbonate tablets: 250 mg, 300 mg, 400 mg

• Lithium carbonate prolonged-release (modified-release): 200 mg, 400 mg

• Lithium citrate syrup (liquid): 5 mEq/5 mL or 8 mEq/5 mL

• Salt equivalents:

  • 8.12 mmol Li⁺ ≈ 300 mg lithium carbonate

  • 5 mL of lithium citrate ≈ 8 mEq ≈ 300 mg lithium carbonate

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Dosage and Administration

Adult Starting Dose (Bipolar Disorder):

• Initial: 600–900 mg/day (usually in divided doses)

• Adjust based on serum lithium levels, renal function, and clinical response

Maintenance dose:

• Typically 600–1200 mg/day, adjusted to achieve therapeutic levels

• Administer once or twice daily depending on formulation

Target serum lithium levels (12 hours post-dose):

• Acute mania: 0.8–1.2 mmol/L

• Maintenance therapy: 0.6–1.0 mmol/L

• Elderly or sensitive patients: 0.4–0.8 mmol/L

Pediatric use:

• Not routinely recommended under age 12

• Use in adolescents with bipolar disorder must be individualized and closely monitored

Elderly:

• Lower doses due to decreased renal clearance

• Frequent monitoring required

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Pharmacokinetics

• Absorption: Nearly complete oral absorption

• Peak plasma level: 1–3 hours (immediate-release), 4–6 hours (slow-release)

• Distribution: Widely distributed; does not bind to plasma proteins

• Metabolism: Not metabolized; active as lithium ion (Li⁺)

• Elimination: Excreted unchanged by the kidneys

• Half-life:

  • Adults: 18–24 hours

  • Elderly: 36 hours or more

• Steady state: Achieved after 5–7 days

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Contraindications

• Hypersensitivity to lithium or excipients

• Severe renal impairment

• Significant cardiovascular disease (e.g., sick sinus syndrome)

• Sodium depletion or dehydration

• Addison’s disease

• Untreated hypothyroidism

• Pregnancy (particularly first trimester, unless benefits outweigh risks)

• Breastfeeding (lithium is excreted in breast milk)

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Warnings and Precautions

1. Narrow Therapeutic Index:

   • Toxicity can occur at therapeutic levels (especially >1.5 mmol/L)

2. Renal Function:

   • Lithium accumulates in renal impairment; monitor creatinine and eGFR

   • Risk of nephrogenic diabetes insipidus and chronic interstitial nephritis with long-term use

3. Thyroid Function:

   • May cause hypothyroidism or goiter

   • Monitor TSH, free T4 at baseline and every 6–12 months

4. Electrolyte Balance:

   • Sodium and fluid status critically influence lithium levels

   • Hyponatremia, dehydration, diuretics can precipitate toxicity

5. Cardiac Effects:

   • May cause ECG changes (T wave flattening, arrhythmias)

   • Avoid in bradyarrhythmias or sick sinus syndrome

6. CNS Effects:

   • Tremor, memory issues, or slowed cognition may occur

7. Dermatologic Effects:

   • Acne, psoriasis exacerbation, dry skin

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Adverse Effects

Common:

• Fine hand tremor

• Polyuria and polydipsia (nephrogenic diabetes insipidus)

• Weight gain

• Nausea, metallic taste

• Fatigue, cognitive dulling

• Dermatologic: acne, psoriasis

Less Common/Rare:

• Hypothyroidism

• Hyperparathyroidism and hypercalcemia

• Bradycardia

• Leukocytosis (benign)

• Nephropathy with long-term use

• Seizures (in toxicity)

• Coma (in overdose)

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Drug Interactions

Increased Lithium Levels (Toxicity Risk):

• NSAIDs (especially indomethacin, ibuprofen, diclofenac)

• ACE inhibitors (enalapril, lisinopril)

• ARBs (losartan, valsartan)

• Thiazide diuretics (hydrochlorothiazide)

• Loop diuretics (less than thiazides, but still risky)

• COX-2 inhibitors

• Low sodium diets or dehydration

Decreased Lithium Levels:

• Caffeine

• Theophylline

• High sodium intake

Other Cautionary Combinations:

• Antipsychotics (especially clozapine, haloperidol): Risk of neurotoxicity

• SSRIs or TCAs: Risk of serotonin syndrome (rare but serious)

• Carbamazepine: May increase neurotoxicity

• Methyldopa or verapamil: Additive CNS effects

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Toxicity and Overdose

Therapeutic range: 0.6–1.0 mmol/L
Toxicity threshold: >1.5 mmol/L
Severe toxicity: >2.5 mmol/L

Symptoms of Toxicity:

• Mild (1.5–2.0 mmol/L):

  • Nausea, vomiting, tremor, lethargy, diarrhea

• Moderate (2.0–2.5 mmol/L):

  • Confusion, ataxia, dysarthria, muscle weakness

• Severe (>2.5 mmol/L):

  • Seizures, stupor, coma, cardiac arrhythmia, death

Management:

• Discontinue lithium immediately

• IV fluids to enhance excretion

• Hemodialysis if:

  • Serum lithium >4.0 mmol/L (acute)

  • 2.5 mmol/L with symptoms

  • Renal failure present

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Monitoring Parameters

Parameter	Frequency
Serum lithium level	5–7 days after dose change; then every 3 months
Renal function (eGFR, creatinine)	Baseline, then every 6–12 months
Thyroid function (TSH, FT4)	Baseline, then every 6–12 months
Electrolytes (Na⁺, K⁺, Ca²⁺)	Periodically
ECG (if cardiac risk factors)	Baseline, then as needed
Weight, hydration status	Every visit

Pregnancy and Lactation

Pregnancy:

• Category D (FDA):

  • Crosses placenta; associated with Ebstein’s anomaly (rare heart defect)

  • Risk of fetal nephrotoxicity, hypothyroidism, low birth weight

  • May be used in high-risk bipolar patients if alternative treatments fail

Lactation:

• Excreted in breast milk in significant amounts

  • Risk of toxicity (hypotonia, cyanosis, renal dysfunction) in neonates

  • Breastfeeding generally not recommended

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Patient Counseling Points

• Take with food or milk to reduce GI upset

• Maintain consistent salt and fluid intake (do not restrict sodium unless advised)

• Avoid dehydration (hot weather, exercise, vomiting/diarrhea)

• Do not change brands or dosage forms without consulting a physician

• Report symptoms of toxicity: tremor, confusion, vomiting, diarrhea, slurred speech

• Avoid over-the-counter NSAIDs and diuretics unless approved

• Importance of regular blood tests

• Do not stop abruptly, especially in long-term therapy

• Use effective contraception if of childbearing potential

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Storage and Stability

• Store at 20–25°C

• Protect from moisture and light

• Keep out of reach of children