What could be the cause of hyperammonemia in a patient with bipolar disorder and a history of cocaine use?

Elevated Ammonia in Bipolar Disorder with Cocaine Use

The most likely cause of hyperammonemia in this patient is medication-induced, specifically from mood stabilizers such as valproic acid or carbamazepine commonly used to treat bipolar disorder. 1, 2, 3

Primary Medication-Related Causes

Valproic acid is the most common culprit, causing hyperammonemia through direct inhibition of the urea cycle, and can occur even at therapeutic drug levels without hepatic dysfunction. 1, 3, 4 This mechanism is distinct from liver toxicity—patients can develop severe hyperammonemia (levels >300 μmol/L) with completely normal liver function tests. 4

• Carbamazepine represents another mood stabilizer that causes hyperammonemia in bipolar patients, typically manifesting 3 weeks after initiation with agitation and elevated ammonia despite therapeutic drug levels and normal liver enzymes. 2
• The hyperammonemia from these medications can present with altered mental status, coma, or aggressive behavior even when liver function remains intact. 3, 4

Cocaine Use Considerations

Cocaine itself does not directly cause hyperammonemia. 5 The cardiovascular and neurological complications of cocaine (coronary vasospasm, acute coronary syndrome, seizures) are well-documented, but ammonia elevation is not among them. 5

• However, cocaine use in bipolar patients is associated with medication non-compliance, which could paradoxically worsen underlying metabolic issues or lead to erratic dosing of ammonia-elevating medications. 6

Diagnostic Algorithm

Check the following in this specific order:

1. Obtain serum ammonia level with proper collection technique—use EDTA tube, place immediately on ice, transport within 60-90 minutes to avoid false elevation. 7

2. Measure valproic acid and carbamazepine levels if patient is on these medications, recognizing that hyperammonemia occurs at therapeutic concentrations. 2, 3, 4

3. Check complete liver function panel—but recognize that normal transaminases do NOT exclude medication-induced hyperammonemia. 4

4. If ammonia is elevated with normal liver enzymes, this pattern strongly suggests medication effect or underlying urea cycle enzymopathy unmasked by valproic acid. 3, 4

Secondary Considerations

If medication history is negative or ammonia remains unexplained:

• Congenital portosystemic shunts can present in adulthood (even 6th-7th decade) with recurrent encephalopathy and normal liver enzymes—diagnose with MRI. 7
• Underlying urea cycle disorder (particularly partial ornithine transcarbamylase deficiency) may be unmasked by valproic acid therapy, presenting for the first time in adulthood. 1, 3
• Acute kidney injury impairs ammonia excretion and should be excluded with creatinine measurement. 1

Critical Pitfalls to Avoid

Do not assume normal liver function tests exclude medication-induced hyperammonemia—this is the most common diagnostic error, as valproic acid and carbamazepine cause hyperammonemia through urea cycle inhibition independent of hepatotoxicity. 3, 4

• Do not attribute altered mental status solely to cocaine intoxication or psychiatric decompensation without checking ammonia—this delays recognition of a treatable metabolic emergency. 2, 3
• Do not continue the offending mood stabilizer once hyperammonemia is identified—discontinuation results in rapid clinical recovery within 4 days. 2, 3

Immediate Management if Hyperammonemia Confirmed

Stop the offending medication immediately (valproic acid or carbamazepine) as this is the definitive treatment. 2, 3

• Initiate oral lactulose to reduce ammonia absorption from the gut. 2
• Consider L-carnitine 50 mg/kg loading dose if ammonia >100 μmol/L, as it facilitates ammonia metabolism. 8
• Monitor ammonia levels every 3-4 hours until normalized. 8
• Switch to alternative mood stabilizer (such as lamotrigine, which does not cause hyperammonemia) once acute episode resolves. 2, 9