Clozapine Intoxication in a Patient with Lamotrigine-Induced Rash

Clozapine and lamotrigine are an effective combination in the therapy for treatment-resistant bipolar disorder [2]. These compounds are metabolized via different emzymatic pathways and their coadministration is thought to be free of relevant pharmacokinetic interactions. There was one case report published showing an elevated clozapine plasma level with lamotrigine co-medication [5]. However, both compounds are associated with severe side effects: clozapine is known to have an increased risk of agranulocytosis compared to other atypical antipsychotics and lamotrigine may cause severe skin rash and life-threatening Stevens-Johnson syndrome. We report the case of a 43-year-old male patient with extremely elevated clozapine plasma levels, clinical signs of a clozapine intoxication and a severe drug-induced skin rash while on a combination of clozapine and lamotrigine. This case was assessed within the AMSP study for the assessment of severe adverse drug reactions [3].

Mr. R had a 24-year history of bipolar disorder. Because of unresponsiveness to lithium, valproic acid and several atypical antipsychotics he finally received clozapine (300–400 mg/day) for the last four years and in this time clozapine plasma levels were checked regularly and turned out to be stable (between 400 and 500 ng/mL) even during several upper respiratory tract infections. One month before admission to our hospital the clozapine plasma level was at 452 ng/mL at an oral dose of 350 mg/d.

He was admitted to our department because of a severe depressive episode. Treatment with clozapine was continued (350 mg/day) and therapy with lamotrigine was initiated. The dose of lamotrigine was titrated up to 50 mg in steps of 25 mg/week. On day 13 after admission and initiation of lamotrigine he complained about dizziness. At this time he received clozapine (350 mg/d), lamotrigine (50 mg/d) and lorazepam (2–3.5 mg/d). The next day his temperature increased up to 39.2 °C and he became disorientated. His state worsened and on day 15 he developed a confluent rash of the trunk with facial involvement. Clozapine plasma level at this time (quantified by tandem mass spectrometry) was measured with 2 427 ng/mL (norclozapine 708 ng/dL), lamotrigine with 1.1 mg/L and CRP with 8.8 mg/dL, all other laboratory data including white blood cell count stayed within normal ranges and also virological and serological findings showed no evidence of an ongoing viral infection.

As there were neither signs of muscle rigidity nor elevation of creatine phosphokinase (CPK) was detected in the laboratory findings a neuroleptic malignant syndrome could be ruled out. Lamotrigine-associated skin rash typically occurs at the onset of treatment after rapid dose escalation but has also been reported at lower plasma levels and the consulted dermatologist assessed the skin rash as caused by lamotrigine. Clozapine, lamotrigine and lorazepam were discontinued. On day 18 after admission to the hospital the clozapine level reached 1 175 ng/mL (norclozapine 526 ng/mL) and on day 22 the clozapine level had dropped to 48 ng/mL (norclozapine 78 ng/mL) and CRP to 0.34 mg/dL. At day 28 he received again clozapine at an oral dose of 100 mg/d and 2 days later the level reached 119 ng/mL (norclozapine 83 ng/mL) ([Table 1]).

Table 1 Time course of medications and plasma levels. −27α 0β 7χ 15χ 18χ 22χ 28χ 30χ α days before admission to the hospital; β admission to the hospital; χ days after admission to the hospital * Daily dose in mg/day; # ng/mL; ° mg/L clozapine* 350 0 100 lamotrigine* 25 50 0 lorazepam* 2–3.5 2 plasma levels clozapine# 452 2 472 1 175 48 119 norclozapine# 276 708 526 78 83 lamotrigine° 1.1

This patient suffered from two severe adverse drug reactions at the same time: a) an allergic rash following initiation of therapy with lamotrigine and b) dizziness following extremely elevated clozapine levels. How can this extreme rise in clozapine plasma levels be explained? There were no changes in smoking behaviour and the patient had never experienced a drug-induced rash before. Clozapine is metabolized to its active metabolite norclozapine (and clozapine N-oxide) by cytochrome P450 (CYP450) 1A2 and to a lesser extent 2D6, 3A4, 2C9 and 2C19. The active compounds clozapine and norclozapine [1] are further glucuronidated by uridine 5′-diphosphate glucuronosyltransferases (UGT) 1A4 (and 1A3). Lamotrigine was reported to be metabolized by UGT1A4. As both clozapine and lamotrigine use UGT1A4, in a similar case [5] it was speculated by Wynn et al. [8] that the rise in clozapine and norclozapine may be due to a competitive inhibition of the conjugate. But it is unclear whether this could explain such a drastic increase in the clozapine plasma level.

On the other hand it is known that during infectious diseases pro-inflammatory cytokines may inhibit CYP450 and glucuronidation-dependent drug metabolism and a rise of clozapine levels during acute infections has already been reported [7]. Furthermore, clozapine itself was shown to be able to induce pro-inflammatory cytokines [6]. But this case differs in one important point: The patient did not suffer from an acute infection but from a severe drug-induced rash and the cytokine pattern in drug hypersensitivity reaction [interleukin (IL)-3, tumour necrosis factor (TNF)-α, TNF-β] is distinct from the pro-inflammatory cytokine pattern seen in acute infectious states. Especially pro-inflammatory cytokins (IL-1, IL-6), but not TNF-β or IL-3, have been seen to inhibit cytochrome p450 enzymes. So one could speculate that also cytokines involved in lamotrigine-induced skin reaction – arising days before a drug-induced rash may be clinically detected − may inhibit enzymes of the CYP450 and UGT system involved in clozapine metabolism, causing this extreme rise in clozapine plasma levels. As a consequence it may be advisable to check clozapine levels in subjects receiving lamotrigine, in particular in those with a risk profile for lamotrigine-induced rash [history of antiepileptic drug (AED) induced rash, allergic rash to a non-AED, comedication of valproic acid] [4] and to adhere to the recommended slow titration scheme for lamotrigine.

References

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