LAUSR

I read with interest the paper by Cornelis et al. [1], addressing the issue of quetiapine abuse in persistent insomnia disorder. The authors described an interesting case of dependence developing in course of the treatment emphasising the risk of abuse and importance of patient monitoring. The core hypothesis of Cornelis et al. on the phenomena described in the case report on a male patient is that sedative effect of quetiapine accumulating with the dose may be risk factor for abuse and dose escalation [1]. As quetiapine abuse and dependence were previously seen in subjects taking up to 2400 mg/d [2] the pharmacodynamics is of vital interest. However, my impression of this interesting paper was that the important issues of pharmacokinetics, drug tolerance and sex of the patient have not been sufficiently addressed. Quetiapine metabolism is mediated by human cytochromes P450 (CYP), with CYP3A4 reported as having a dominant role [3]. Thus, the pharmacokinetic interactions may occur in patients receiving analgesics, antiarrythmics, antibiotics, antiepileptics, antihistamines, antineoplasm, antiparkinsonian drugs, antiprogesterone agents, antirejection drugs, β-blockers, calcium-channel blockers, HMG-CoA reductase inhibitors, nonnucleoside reverse transcriptase inhibitors, protease inhibitors, proton pump inhibitors, steroids, triptans [4]. Drug interactions were considered by the authors and they stated the patient did not take any concomitant medications or herbal products. However, the endocrine factors need closer attention. They are prominent in drugs metabolised via CYP3A4 most probably due to the action of sex hormones and higher plasma concentrations of free testosterone in male subject which may contribute to higher CYP3A4 activity. Thus, the exposure to testosterone in male patients may activate the biotransformation of a number of CYP3A4 substrates, including quetiapine [1,4]. The hypothesis that patients may misuse and abuse quetiapine is substantiated by data from large clinical trials demonstrating sedative and anxiolytic characteristics at doses as low as 300 mg/day [2]. Quetiapine seem to exhibit less sedating activity than other antipsychotic in its class, yet is the only one described in the literature as a drug of abuse or misuse. However, the drug has fewer undesirable side effects such as dystonia and extrapyramidal symptoms, thus explaining why it is abused whilst other antipsychotics are not [2]. Sex also needs to be considered as susceptibility factor for drug misuse. In scope of the emerging issues on quetiapine abuse the evidence that the consideration of pharmacokinetics can improve quetiapine pharmacotherapy in persistent insomnia with regard to efficacy and safety is of vital importance.