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Difficulty: MediumPsychopharmacology and Psychological Therapies

A 26-year-old woman is evaluated in the emergency department for a painful rash, fever, and generalized malaise that began two days ago. She has a history of bipolar I disorder that has been stable for two years on a maintenance regimen of divalproex sodium. Six weeks ago, she experienced a major depressive episode, and her psychiatrist initiated an additional mood-stabilizing medication. The new medication was started at a standard dose of 25 mg daily for two weeks, followed by an increase to 50 mg daily. On physical examination, her temperature is 38.6°C (101.5°F). There is a widespread, erythematous, maculopapular eruption on her face, trunk, and extremities, with scattered areas of epidermal sloughing. Painful erosions are present on her buccal mucosa. Which of the following pharmacokinetic effects of the patient's maintenance medication on the newly added drug most likely precipitated this patient's current condition?

  1. A
    Synergistic blockade of voltage-gated sodium channels
  2. B
    Induction of cytochrome P450 isoenzymes
  3. C
    Decreased renal tubular clearance
  4. Inhibition of hepatic glucuronidationAnswer
  5. E
    Displacement from plasma protein binding sites

Answer

Inhibition of hepatic glucuronidation
The patient's presentation of fever, widespread epidermal sloughing, and mucosal erosions is highly characteristic of Stevens-Johnson syndrome (SJS). In psychiatric practice, lamotrigine is notorious for causing SJS, particularly if titrated too rapidly. This patient was on maintenance divalproex sodium (valproate) and was started on a standard lamotrigine titration schedule. Valproate is a potent inhibitor of UDP-glucuronosyltransferase (UGT), the hepatic enzyme responsible for metabolizing lamotrigine. By inhibiting glucuronidation, valproate roughly doubles the half-life and serum concentration of lamotrigine. To prevent SJS, patients taking valproate must be started on a modified, slower lamotrigine titration schedule (typically 25 mg every other day for the first two weeks). The failure to account for this pharmacokinetic inhibition resulted in rapid lamotrigine accumulation and subsequent SJS.

Step-by-Step Solution

1
Identify the patient's clinical presentation.
The patient has fever, malaise, a widespread maculopapular rash with epidermal sloughing, and mucosal erosions.
These findings are the classic presentation of Stevens-Johnson syndrome (SJS), a life-threatening mucocutaneous reaction.
2
Determine the most likely offending agent based on the psychiatric history.
The patient was recently started on a new mood stabilizer for bipolar depression. Given the risk of SJS, the new medication is almost certainly lamotrigine.
Lamotrigine is a first-line agent for bipolar depression and carries a black box warning for serious skin rashes, including SJS.
3
Analyze the drug-drug interaction occurring with the patient's maintenance medication.
The patient is on maintenance divalproex sodium (valproate). Valproate inhibits UDP-glucuronosyltransferase (UGT).
UGT is the primary enzyme responsible for the hepatic metabolism of lamotrigine.
4
Connect the pharmacokinetic interaction to the clinical outcome.
Because valproate inhibits UGT, lamotrigine clearance is reduced and its half-life is doubled. The psychiatrist used a standard titration schedule instead of the required slower schedule (e.g., 25 mg every other day), leading to toxic lamotrigine levels and precipitating SJS.
Rapid dose escalation of lamotrigine, especially in the presence of a UGT inhibitor like valproate, drastically increases the risk of SJS.

Key Concept

Valproate inhibits hepatic glucuronidation (via UGT enzymes), which doubles the half-life of lamotrigine. When co-administering these medications, the lamotrigine titration schedule must be slowed by 50% to mitigate the risk of Stevens-Johnson syndrome.
Estimated Time:1m 30s
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Topics

Psychopharmacology and Psychological Therapies

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