What are the recommended lithium starting dose, titration schedule, target serum levels, monitoring parameters, side effects, contraindications, and alternative mood stabilizers for an adult with bipolar disorder?

Lithium for Bipolar Disorder: Comprehensive Treatment Guide

Starting Dose and Titration

For adults with bipolar disorder, initiate lithium at 300 mg three times daily (900 mg/day total) and increase by 300 mg weekly until achieving therapeutic serum levels of 0.8-1.2 mEq/L for acute mania or 0.6-1.0 mEq/L for maintenance therapy. 1, 2

Dosing Algorithm:

• Week 1: Start 300 mg TID (900 mg/day) 1
• Week 2: Check lithium level 5 days after reaching steady state; adjust dose to target 0.8-1.2 mEq/L for acute treatment 1, 2
• Acute phase: Monitor lithium levels twice weekly until both laboratory values and clinical symptoms stabilize 1, 2
• Maintenance phase: Target 0.6-1.0 mEq/L; some patients respond at lower concentrations but therapeutic monitoring guides optimization 1, 2

Special Populations:

• Augmentation therapy (e.g., treatment-resistant depression): 150-300 mg/day targeting 0.2-0.6 mEq/L 2
• Elderly or Alzheimer's patients: 150-300 mg/day targeting 0.2-0.6 mEq/L 1
• Age ≥12 years: FDA-approved for both acute mania and maintenance 1, 2

---

Target Serum Levels and Monitoring

Therapeutic Ranges:

• Acute mania/mixed episodes: 0.8-1.2 mEq/L 1, 2
• Maintenance therapy: 0.6-1.0 mEq/L 1, 2
• Augmentation/elderly: 0.2-0.6 mEq/L 1, 2

Monitoring Schedule:

Baseline (before starting lithium): 1, 2

• Complete blood count
• Thyroid function tests (TSH, free T4)
• Urinalysis
• Blood urea nitrogen (BUN) and creatinine
• Serum calcium
• Pregnancy test (females of childbearing potential)

Acute phase: 1, 2

• Lithium level twice weekly until stable
• Clinical assessment weekly

Maintenance phase (every 3-6 months): 1, 2

• Lithium level
• Renal function (BUN, creatinine)
• Thyroid function (TSH)
• Urinalysis

---

Side Effects

Common Side Effects:

• Fine tremor 1
• Nausea 1
• Diarrhea 1
• Polyuria/polydipsia 1
• Weight gain 1

Serious Adverse Effects Requiring Immediate Attention:

• Lithium toxicity signs: Coarse tremor, confusion, ataxia, seizures 1
• Hypothyroidism (monitor TSH every 3-6 months) 1, 2
• Renal impairment (monitor creatinine every 3-6 months) 1, 2

Patient Education on Toxicity:

Educate patients and families to recognize early toxicity signs (fine tremor, nausea, diarrhea) and seek immediate medical attention for severe symptoms (coarse tremor, confusion, ataxia). 1

---

Contraindications and Precautions

Absolute Requirements:

• Lithium should only be initiated where close clinical and laboratory monitoring are available due to its narrow therapeutic window 2
• Adequate renal function required (assess baseline creatinine) 1, 2
• Avoid in severe renal impairment 2

High-Risk Situations:

• Suicide risk: Lithium overdoses can be lethal; implement third-party medication supervision, prescribe limited quantities with frequent refills, and engage family members to restrict access to lethal quantities 1
• Pregnancy: Requires specialized consultation; lithium carries teratogenic risks but may be continued with careful monitoring in some cases 3

Critical Safety Measures:

• Maintain adequate hydration and salt intake 1
• Avoid NSAIDs and diuretics that can increase lithium levels 4
• Never discontinue lithium abruptly—taper over 2-4 weeks minimum to prevent rebound mania (>90% relapse rate with abrupt discontinuation) 1, 2

---

Clinical Efficacy and Evidence Base

Acute Mania:

• Response rates: 38-62% 1
• Lithium has convincingly demonstrated antimanic efficacy but has limited place as monotherapy in severe agitation due to slower onset compared to antipsychotics 5
• Combination with atypical antipsychotics provides superior acute control 1

Maintenance Therapy:

Lithium is the only drug proven efficacious in preventing any mood episodes, manic episodes, and depressive episodes in randomized trials not enriched for prior lithium response—it should be considered the single preferred first-line drug for long-term treatment of bipolar disorder. 6, 7

• Superior evidence for long-term efficacy compared to all other mood stabilizers 1, 6
• Prevents both manic and depressive episodes 1, 5
• Continue for at least 12-24 months after mood stabilization; some patients require lifelong treatment 1, 2
• Withdrawal within 6 months dramatically increases relapse risk 1, 2

Unique Anti-Suicide Effect:

Lithium reduces suicide attempts 8.6-fold and completed suicides 9-fold—an effect independent of its mood-stabilizing properties. 1, 7

---

Alternative Mood Stabilizers

First-Line Alternatives:

Valproate (Divalproex): 1

• Start 125 mg BID, titrate to 50-100 μg/mL
• Particularly effective for mixed episodes, irritability, and rapid cycling
• Higher response rates (53%) than lithium (38%) in children/adolescents
• Requires liver function and CBC monitoring every 3-6 months

Atypical Antipsychotics: 1, 8

• Aripiprazole 5-15 mg/day
• Olanzapine 5-20 mg/day
• Quetiapine 400-800 mg/day
• Risperidone 2-6 mg/day
• Provide more rapid symptom control than lithium alone
• Require metabolic monitoring (BMI, glucose, lipids)

Lamotrigine: 1, 8

• Approved for maintenance therapy in adults
• Particularly effective for preventing depressive episodes
• Not indicated for acute mania
• Requires slow titration (start 25 mg/day, increase by 25-50 mg every 1-2 weeks) to minimize Stevens-Johnson syndrome risk

Combination Strategies:

For severe presentations or treatment-resistant cases, combine lithium or valproate with an atypical antipsychotic—this provides superior efficacy compared to monotherapy. 1

---

Common Pitfalls to Avoid

• Inadequate trial duration: Require 6-8 weeks at therapeutic levels before concluding ineffectiveness 1
• Premature discontinuation: >90% of noncompliant patients relapse vs. 37.5% of compliant patients 1
• Rapid discontinuation: Always taper over 2-4 weeks minimum 1, 2
• Insufficient monitoring: Failure to check levels and organ function leads to toxicity or subtherapeutic dosing 1, 2
• Ignoring drug interactions: NSAIDs, diuretics, and ACE inhibitors increase lithium levels 4
• Overlooking dehydration risk: Educate patients to maintain fluid/salt intake and avoid excessive sweating 1

---

Prolonged-Release vs. Immediate-Release Formulations

Prolonged-release lithium formulations offer consistent serum concentrations, fewer adverse events (particularly GI side effects), and improved adherence compared to immediate-release formulations. 4

• PR formulations allow once-daily dosing
• Reduced peak-to-trough fluctuations minimize side effects
• Consider PR formulations to enhance tolerability and adherence 4