What are the signs of toxicity in a patient with bipolar disorder on lithium (lithium carbonate) therapy?

Signs of Lithium Toxicity in Bipolar Disorder

Lithium toxicity presents along a spectrum from early warning signs to life-threatening multi-organ dysfunction, with symptoms correlating with serum levels but importantly can occur even within therapeutic ranges, particularly in chronic toxicity. 1, 2

Early Warning Signs (Serum Levels <2.0 mEq/L)

Patients and families must be instructed to discontinue lithium immediately and seek medical attention if any of these early signs appear: 1

• Gastrointestinal symptoms: Diarrhea, vomiting, nausea, anorexia 1
• Neuromuscular symptoms: Fine hand tremor (may progress to coarse tremor), muscular weakness, lack of coordination 1, 2
• Neurological symptoms: Drowsiness, mild ataxia, slurred speech 1, 3
• Renal symptoms: Polyuria, mild thirst 1

These early signs can occur at lithium levels below 2.0 mEq/L and in sensitive patients may appear at levels below 1.5 mEq/L. 1

Moderate Toxicity (Serum Levels 2.0-2.5 mEq/L)

As toxicity progresses, additional symptoms emerge: 1

• Neurological deterioration: Giddiness, ataxia, blurred vision, tinnitus 1
• Renal dysfunction: Large output of dilute urine (nephrogenic diabetes insipidus) 1, 4
• Neuromuscular progression: Muscle hyperirritability (fasciculations, twitching, clonic movements), hyperactive deep tendon reflexes 1
• CNS symptoms: Confusion, psychomotor retardation, restlessness, vertigo, dizziness 1

Severe Toxicity (Serum Levels >3.0 mEq/L)

Serum lithium levels above 3.0 mEq/L produce a complex clinical picture involving multiple organs and organ systems: 1

• Severe CNS toxicity: Stupor, coma, seizures, blackout spells, incontinence of urine or feces, somnolence 1
• Cardiovascular toxicity: Cardiac arrhythmias, hypotension, peripheral circulatory collapse, sinus node dysfunction with severe bradycardia (potentially causing syncope) 1, 5
• Neurological emergencies: Acute dystonia, downbeat nystagmus, choreo-athetotic movements 1
• Renal failure: Oliguria, elevated creatinine and BUN 6
• Metabolic derangement: Dehydration, electrolyte imbalances 6

Critical Clinical Pitfall: Toxicity Within Therapeutic Ranges

Lithium toxicity can occur even when serum levels are within the therapeutic range (0.6-1.2 mEq/L), particularly in chronic toxicity or with drug interactions. 6, 2, 3

• A 59-year-old patient developed lithium toxicity with a level of 1.2 mEq/L (therapeutic range) after Valsartan dose increase, presenting with confusion, tremor, gait abnormality, autonomic instability, rigidity, elevated CK (6008), leukocytosis (WBC 22), and renal impairment (Creatinine 4.1). 6
• A 62-year-old patient stable on lithium for 20 years developed coarse tremor and clinical toxicity with normal serum lithium levels in the setting of stage 3 chronic kidney disease. 2
• A 50-year-old patient developed neurotoxicity (dysarthria, past pointing, dysdiadochokinesis, slurring of speech) at a lithium level of 0.9 mEq/L, with persistent neurological deficits at 2-month follow-up despite lithium discontinuation. 3

Therefore, clinicians must treat clinical signs of toxicity even when serum levels appear therapeutic, particularly in patients with renal impairment, drug interactions (ACE inhibitors, NSAIDs, diuretics), or volume depletion. 1, 6, 2

Rare but Serious Complications

• Neuroleptic Malignant Syndrome (NMS): Lithium toxicity can precipitate NMS, characterized by autonomic instability, confusion, rigidity, elevated CK, leukocytosis, and fever. 6
• Cardiotoxicity: Dysrhythmias, cardiomyopathies, myocardial infarction (rarely reported). 5
• Pseudotumor cerebri: Increased intracranial pressure and papilledema; if undetected, can lead to blindness from optic atrophy. 1
• Irreversible neurological damage: Persistent cerebellar dysfunction, particularly with chronic toxicity or delayed recognition. 4, 3

Monitoring Algorithm to Prevent Toxicity

The American Academy of Child and Adolescent Psychiatry recommends baseline and ongoing monitoring: 7, 8

• Baseline: Complete blood count, thyroid function tests, urinalysis, BUN, creatinine, serum calcium, pregnancy test in females 7, 8
• Ongoing: Lithium levels, renal function, thyroid function every 3-6 months 7, 8
• Target therapeutic range: 0.8-1.2 mEq/L for acute treatment; 0.6-1.0 mEq/L for maintenance 7
• Serum levels should not exceed 2.0 mEq/L during acute treatment 1

Risk Factors That Lower Toxicity Threshold

• Renal impairment: Chronic kidney disease reduces lithium clearance 6, 2, 4
• Volume depletion: From sweating, diarrhea, vomiting, or inadequate fluid intake 1, 4
• Drug interactions: ACE inhibitors (Valsartan), NSAIDs, diuretics increase lithium levels 1, 6
• Elderly patients: Reduced renal function and total body water 4
• Intercurrent illness: Fever, infection, dehydration 1, 4

Essential Patient Education

Outpatients and families must be warned to discontinue lithium and contact their physician immediately if these clinical signs appear: 1

• Diarrhea, vomiting, tremor (especially coarse tremor)
• Mild ataxia, drowsiness, muscular weakness
• Confusion, slurred speech, gait abnormality

Patients must maintain normal diet including salt and adequate fluid intake (2500-3000 mL daily) during stabilization. 1