Here are the basic facts that rescue the dramatic headline from being mere hyperbole:
1. Some of the drugs used to treat schizophrenia are associated with increased rates of sudden cardiac death ;
2. The 2 schizophrenia drugs associated with the highest rates of sudden cardiac death are metabolized by CYP2D6 ;
3. 7% of the normal population have genetic mutations that reduce the activity of CYP2D6;
4. One of the most commonly used anti-fungal treatments, Lamisil® (terbinafine), is a potent inhibitor of the enzyme CYP2D6 .
We are continuing our exploration of psychiatry drugs and the potential need for increased biomarker-awareness by looking at a case study of one particularly risky psychiatry drug in BiomarkerBase™ that has a clinical biomarker association.
Thioridazine is a drug that was marketed in the US by Novartis as Mellaril® until 1995, after which generics became the available form of the drug. Thioridazine is called a “typical” drug in the psychiatric field. At one time it was one of the most commonly prescribed psychiatry drugs, used for indications as broad as learning disabilities .
Thioridazine has also been suspected of causing an increased QT interval in electrocardiogram measurements, leading to life-threatening ventricular arrhythmias. Because of these concerns, the drug is only indicated as a second line schizophrenia treatment in the US and UK (which originally caused some consternation in the psychiatric community) .
The concerns about thioridazine seem to have been confirmed by a 2009 study published in the New England Journal of Medicine that found patients taking thioridazine had a threefold higher rate of sudden death than the reference group . Thioridazine now has a black box warning regarding the risks of arrhythmias and sudden death.
Thioridazine is metabolized by CYP2D6, and its drug label includes contraindications for thioridazine in combination with CYP2D6 inhibitors , because “elevated levels of thioridazine would be expected to augment the prolongation of the QTc interval associated with thioridazine and may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as Torsades de pointes type arrhythmias.” Thioridazine is also contraindicated for CYP2D6 poor-metabolizers, who represent “about 7% of the normal population” . But while ECG measurements are specifically recommended before prescribing thioridazine, testing for CYP2D6 mutations is not. Such testing should be mandatory.
Terbinafine (Lamisil®) was a heavily advertised drug during its patent period, and it remains a very commonly used antifungal drug (generic forms offered by Teva and Roxane alone totaled $685 million in sales in 2007, and over a dozen companies currently manufacture the drug). Terbinafine is also a potent inhibitor of CYP2D6 , although it is not one of the inhibitors mentioned in the contraindications for thioridazine.
Combining a commonly used CYP2D6 inhibitor such as terbinafine with thioridazine in a patient who is genetically a poor CYP2D6 metabolizer would seem to be a very risky proposition.
We were unable to determine how commonly thioridazine is prescribed today, but it is very commonly available through online drug stores. We were also able to find examples of its use in off label indications such as anxiety and depression, so its use could well be less constrained than the FDA and other regulatory bodies would hope given the drug’s safety profile.
Exploration of its uses may well increase as well, as a 2012 study published in Cell found that thioridazine selectively targeted leukemic stem cells in vitro .
This case study for thioridazine is useful for emphasizing, with a potentially life-threatening scenario, the importance of companion diagnostic biomarker testing. Clearly any patient being considered for treatment with thioridazine should be tested for CYP2D6 mutations, particularly when it would be so easy to add an inhibitor to the mix.
1. Ray et al., N Engl J Med 2009;360:225-35.
2. Yasui-Furukori et al., Eur J Clin Pharmacol (2007) 63:51–56.
3. Bateman, et al., Br J Clin Pharmacol. 2003 June; 55(6): 596–603.
4. Letter, “Removal of thioridazine from primary care formulary will result in prescribing vacuum,” BMJ 2001;323:695.1
5. Thioridazine drug label, http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b8d8c29a-414d-4622-bffd-b742725b20f0.
6. Sachlow et al., Cell, Volume 149, Issue 6, 1284-1297, 24 May 2012.