Olanzapine toxicity in unconjugated hyperbilirubinaemia (Gilbert's syndrome)

We have recently observed symptoms of toxicity caused by olanzapine at therapeutic dosages. Olanzapine metabolism was hampered because the patient had idiopathic unconjugated hyperbilirubinaemia (Gilbert's syndrome). As this is a frequent disorder in the general population (occurring in 10% of the European population), we feel that it is important to consider the possibility of Gilbert's syndrome before prescribing olanzapine.

A 19-year-old male with paranoid features and schizophrenic symptoms was treated with 2.5 mg olanzapine for 2 days, which was increased to 5 mg on the third day. On the fourth day, because of a suicide attempt and extreme agitation, the patient was admitted to a psychiatric centre. He was given oral doses of 10 mg olanzapine and 5 mg lorazepam. The patient was conscious on the sixth day but did not respond to verbal stimuli and his symptoms of mutism persisted over the next few days. Communication was possible by monosyllables on day eight. On day ten he was bradypsychic, oriented and capable of articulating short sentences with great effort. Speech returned to normal on day twelve. The patient described his experience as a sensation of not being able to find the words in his head. He had not previously displayed speech alterations, nor did they appear later.

Gilbert's syndrome and Crigler—Najjar syndromes type I and II are familial unconjugated hyperbilirubinaemias caused by genetic lesions involving a single complex locus encoding bilirubin uridine diphosphate — (UDP)-glucuronosyltransferase, which is involved in the detoxification of bilirubin by conjugation with glucuronic acid.

Over the past few years a number of different mutations affecting this gene have been characterised, in which a greater frequency of schizophrenia has been described (Miyaoka et al, 2000). Olanzapine is metabolised in the liver through direct glucuronidation reactions. Polymorphisms in glucuronosyltransferases, which often result in a decreased capacity for bilirubin glucuronidation, may have a significant impact on our capacity to detoxify and eliminate drugs and toxins (Mackenzie et al, 2000). Drug-mediated toxicity caused by genetic deficiency of UPD-glucuronosyl-transferases is known (Burchell et al, 2000), as in the case of the administration of phenothiazine antipsychotics or tricyclic antidepressants. Mutism with olanzapine use has been reported in cases of overdose (Hanel et al, 1998; Cohen, 1999).

The use of therapeutic dosages of olanzapine can cause toxic symptoms if a lack of bilirubin UDP-glucuronosyltransferase is present. We should keep in mind idiopathic unconjugated hyperbilirubinaemia when prescribing olanzapine.