Lithium
Lithium
Generic Name
Lithium
Mechanism
- The mood stabilizer Lithium primarily modulates intracellular signaling pathways:
- Inhibition of phosphatidylinositol (PI) turnover → ↓ IP3/Ca²⁺ release, ↓ neuronal excitability.
- Augmentation of cyclic AMP (cAMP) signaling → normalizes glutamatergic neurotransmission.
- Inhibition of glycogen synthase kinase‑3β (GSK‑3β) → promotes neuroprotection and synaptic plasticity.
- Alteration of vesicular monoamine transporter‑2 (VMAT‑2) → reduces serotonin release.
- The net effect is stabilization of neuronal firing and prevention of manic and depressive recurrences.
Pharmacokinetics
- Absorption: Rapid oral absorption, bioavailability ~90 %. Peak plasma ~2 h.
- Distribution: Widely distributes into tissues; high protein binding (~95 %). Large extracellular volume (~0.8 L/kg).
- Metabolism: Minimal hepatic metabolism; largely exerts activity as the parent ion.
- Excretion: Renal elimination dominates (~85 % unchanged). Clearance ~6–12 mL/min/kg.
- Half‑life: 20–36 h (varies with renal function).
- Factors affecting kinetics:
- *Renal impairment* → ↑ half‑life, ↑ toxicity risk.
- *Sodium loss* or hypernatremia → ↑ plasma lithium.
- *NSAIDs, ACE inhibitors, diuretics* → ↓ clearance.
Indications
- Bipolar I Disorder
- Acute mania (therapeutic range 0.6–1.2 mmol/L).
- Maintenance prophylaxis post‑mania or mixed episodes.
- Bipolar II & Cyclothymic Disorder – adjunct or monotherapy for depressive episodes.
- Unipolar depression – adjunct in severe, recurrent forms with limited response.
- Schizoaffective disorder – mood stabilization component.
Contraindications
- Absolute contraindications
- Pregnancy (Category X).
- Severe renal failure (GFR <30 mL/min/1.73 m²).
- Severe dehydration or hypotension.
- Uncontrolled hypothyroidism or hyperthyroidism.
- Relative contraindications
- Severe hepatic dysfunction.
- Addison’s disease.
- Warnings
- Narrow therapeutic index; serum levels must be monitored.
- Excipients (magnesium carbonate) can alter absorption – avoid calcium/magnesium‑rich products.
- Possible teratogenicity → avoid in women planning pregnancy.
- Drug interactions
- NSAIDs, ACE inhibitors, ARBs, diuretics ↑ serum lithium.
- Tricyclic antidepressants, SSRIs ↑ neurotoxicity.
- Lithium carbonate + Propanolol → decreased clearance.
Dosing
- Initial loading: 300 mg po q12h (or 600 mg/d) for rapid effect.
- Titration: Increase by 300 mg/day increments, aiming for trough serum 0.6–1.2 mmol/L.
- Maintenance: 900–1 200 mg/day divided q12h (≈ 0.6–1.0 mmol/L). Adjust for renal function, age, comorbidities.
- Long‑term: Typically taken daily 24–hr. Compliance education critical.
Adverse Effects
| Class | Adverse Effect | Comment |
| Neurologic | Fine tremor, sedation, ataxia, dizziness | Mild doses → tremor; monitor at higher troughs |
| Gastrointestinal | Nausea, vomiting, diarrhea, anorexia | Consider antihistamines, antiemetics |
| Endocrine | Thyroid enlargement, hypothyroidism, hyperthyroidism | Thyroid imaging sometimes required |
| Renal | Urinary frequency, nephrogenic diabetes insipidus, interstitial nephritis | Monitor renal function, urine output |
| Cardiac | Arrhythmias, hyperkalemia (especially with ACE inhibitors) | ECG if symptomatic |
| Psychiatric | Cognitive blunting, mood lability | Monitor with rating scales |
| Dermatologic | Acne, rash, photosensitivity | Treat with topical agents |
| Serious | Lithium toxicity (Encephalopathy, seizures, arrhythmia), renal failure, acute kidney injury | Symptoms: nausea, vomiting, tremor, hyperreflexia, seizure, coma |
Monitoring
| Parameter | Frequency | Rationale |
| Serum Lithium Concentration | 5 days after dose change, then 2–4 weeks initially, quarterly thereafter | Prevent toxicity, ensure therapeutic range |
| Serum Sodium | With a lithium level check | Hyponatremia ↑ lithium levels |
| Renal Function (Scr, eGFR) | 2–4 weeks after initiation, then every 3–6 months | Renal clearance pivotal for dosing |
| Thyroid Function (TSH, T4) | 3–6 months after initiation, then annually | Lithium induces thyroid dysfunction |
| Blood Pressure, Weight | With each office visit | Sodium/fluid balance monitoring |
| ECG (if symptomatic or baseline abnormality) | Every 6–12 months | Detect arrhythmias |
| CBC | Every 3–6 months | Rare bone marrow suppression |
Clinical Pearls
- Hydration is King: Encourage consistent fluid intake; even mild dehydration can push serum levels into toxic range.
- Sodium Stability: Avoid drastic sodium shifts (e.g., low‑salt diets, high‑salt supplement use). Treat hypernatremia aggressively.
- Drug Interaction Mindset: NSAIDs, ACEI/ARB, thiazide diuretics, and antidepressants can slow clearance—hold or adjust lithium accordingly.
- Child‑Friendly Dose Charts: 300 mg q12h is a good starting block for most adults; children weigh doses 0.3–1 mmol/kg/day.
- Pregnancy Check‑Get‑Scan: Any woman of child‑bearing potential must receive pre‑conception counseling and contraceptive counseling.
- Toxicity First Signs: Early symptoms (nausea, vomiting, tremor, ataxia) should prompt immediate serum level checks.
- Triage of Trough Levels: 0.6–1.0 mmol/L is adequate for mania remission; levels >1.2 mmol/L can be acceptable in refractory cases but increase monitoring.
- Citizen’re: The "Switch" phenomenon: Rapid discontinuation can cause paroxysmal pain, edema, and even seizures; taper slowly under supervision.
Bottom line: Lithium remains the gold‑standard mood stabilizer for bipolar disorders, but its narrow therapeutic window, organ-specific toxicities, and drug interactions mandate diligent monitoring and patient education.