Lithium

Lithium is a psychiatric medication used primarily as a first-line therapy for bipolar disorder. It is also used in treatment-resistant depression to augment antidepressants. The specific mechanism by which lithium acts to stabilize mood is not definitively known, but it is thought to be due to inhibition of the phosphoinositol cascade. Common side effects include gastrointestinal distress (nausea, diarrhea), polyuria, polydipsia, and tremor. Lithium therapy has a very narrow therapeutic index; frequent monitoring is therefore required to prevent toxicity.

• Mechanism of action: While the mechanism of action has not been definitively established, inhibition of the phosphoinositol cascade is thought to result in mood stabilization.
• Steady state: usually reached 4–5 days after initiation or a change in dosage

• 95% of lithium is excreted by the kidneys.
• It is freely filtered at the glomerulus and mostly reabsorbed in the proximal convoluted tubule via sodium channels. ^[1]

• First-line therapy for bipolar disorder
  • Mood stabilization in patients with acute mania
  • Maintenance therapy
• Augmentation in treatment-resistant depression

General adverse effects ^[2]

Adverse effects occur at therapeutic levels (0.4–1.0 mEq/L) but tend to be more severe at peak serum concentration of the drug.

Nonspecific

• Nausea, diarrhea
• Weight gain
• Dry oral mucosa
• Leukocytosis

Motor

• Fine tremor
  • Nonprogessive, symmetric, fine postural tremor in the distal ends of upper extremities
  • Typically occurs when lithium therapy is started or the dose is increased but can occur at any time during the course of treatment
  • Often decreases spontaneously over time
• Muscle weakness

Dermal

• Acne
• Worsening psoriasis
• Hair thinning

Cardiac ^[3]

• ECG changes: T-wave depressions (most common), U waves, repolarization abnormalities
• Sinus node dysfunction (most commonly sinus bradycardia)

Thyroid

• Hypothyroidism (often subclinical)
  • Thyroid function tests should be performed every 6–12 months during ongoing treatment
  • Lithium-induced hypothyroidism, should be treated with replacement therapy (levothyroxine).
  • There is usually no need to discontinue lithium therapy.
• Lithium-induced hyperparathyroidism
  • Caused by the elevation of the calcium-sensing setpoint of the parathyroid glands and induction of parathyroid hormone production
  • Leads to hypercalcemia
• Goiter (particularly in second and third trimester of pregnancy)

Renal

• Nephrogenic diabetes insipidus
  • Pathophysiology: lithium interferes with ADH signaling → ↓ aquaporins (water channels) on the collecting duct cell's surface → ↓ water molecules are reabsorbed and kidneys are unable to concentrate urine → ↑ free water excretion
  • Clinical features: polyuria, nocturia, and polydipsia → ↑ risk of dehydration and subsequent lithium toxicity
• Chronic interstitial nephritis (lithium-associated nephropathy)
  • Interstitial fibrosis, focal nephron atrophy, tubular cysts with chronic use
  • Risk correlates with the cumulative dose and duration of lithium use.
  • Often occurs in the setting of nephrogenic DI
  • Can progress to chronic kidney disease

Lithium toxicity ^[4]

Toxicity occurs at serum levels > 1.5 mEq/L.

Causes

• Increase in dosage (lithium has a narrow therapeutic window)
• Renal impairment from any cause
• Low effective circulating volume (e.g., due to dehydration, loop diuretic use, cirrhosis, congestive heart failure)
• Medications that can precipitate lithium toxicity by increasing renal absorption of lithium:
  • Thiazide diuretics
  • NSAIDs (except aspirin)
  • ACE inhibitors
• Other medications: tetracyclines, cyclosporines, metronidazole

Clinical features

• Gastrointestinal
  • Nausea, vomiting, and diarrhea
  • Further fluid loss may exacerbate lithium toxicity.
• Neuromuscular
  • Altered mental status, confusion
  • Somnolence, coma
  • Delirium, encephalopathy, psychomotor impairment
  • Coarse tremors, seizures, fasciculations, myoclonic jerks,
  • Ataxia, slurred speech, nystagmus
  • Hyperreflexia
• Acute renal failure

LITHIUM: “Lithium can cause Irregular Thyroxine levels (hypothyroidism or hyperthyroidism), Heart (Ebstein anomaly), nephrogenic diabetes Insipidus, and Uncontrolled Muscle movements (tremor).”

Treatment of adverse effects ^[5][6]

• General measures
  • Reassurance, avoidance of exacerbating factors (e.g., caffeine, stress), and follow-up
  • Dosage adjustment
    • Use of short-acting lithium preparations, divided doses, or a different lithium salt (e.g., citrate instead of carbonate)
    • Reducing the total daily dose of lithium if serum lithium concentration is close to the upper limit of the therapeutic range
• Tremor: beta blockers (e.g., propranolol) if persistent or severe tremor
• Nephrogenic diabetes insipidus: amiloride ^[7]
• Lithium toxicity
  • Discontinuation of lithium
  • Hydration with isotonic fluid (0.9% NaCl solution) and electrolyte correction to promote lithium clearance
  • Hemodialysis: first-line treatment for severe lithium toxicity
    • Indications
      • Serum lithium concentration > 5.0 mEq/L
      • Serum lithium concentration > 4.0 mEq/L with kidney dysfunction
      • Altered mental status, seizures, and/or life-threatening arrhythmias
    • Hemodialysis should be continued until serum lithium concentration is < 1.0 mEq/L or for a minimum of 6 hours (if the serum lithium concentration cannot be measured).
  • Ventilatory support if required
  • Whole bowel irrigation with polyethylene glycol can also be considered.
  • Activated charcoal does not prevent the absorption of lithium.

Monitoring serum levels of lithium is important because of its narrow therapeutic window.

We list the most important adverse effects. The selection is not exhaustive.

• Absolute contraindications ^[8][9]
  • Advanced renal failure (creatinine clearance < 30 mL/min)
  • Severe cardiovascular disease
• Relative contraindications
  • Concurrent diuretic use
  • Dehydration, sodium depletion
  • Desired pregnancy/pregnancy: lithium can freely cross the placental barrier, inevitably resulting in fetal lithium exposure
    • ↑ Risk of miscarriage and neonatal complications (e.g., longer duration of hospital stays, higher rate of CNS and neuromuscular complications) ^[10][11]
    • Teratogenicity; (especially in the first trimester): ↑ risk of cardiovascular malformations (in particular Ebstein anomaly)
    • If lithium is needed during pregnancy, aim for the minimum effective dose and monitor serum levels regularly.
    • LARCs are generally the preferred method of contraception because they are easy to use and have low failure rates. ^[12]

Alternative maintenance treatment options for bipolar disorder include lamotrigine, valproate, and carbamazepine. Valproate and antipsychotics (e.g., olanzepine, quetiapine) can be used for treatment of acute mania and hypomania.

Before prescribing lithium to women of child-bearing age, evaluate thyroid function, renal function, and human chorionic gonadotropin levels to rule out pregnancy.

We list the most important contraindications. The selection is not exhaustive.