19. CARDIAC SIDE EFFECTS OF PSYCHOTROPIC MEDICATION: Focus on QTc Prolongation and Toriade de Pantes Cherry Lewin and Peter M. Haddad* 1. INTRODUCTION A wide range of cardiac side effects can occur with psychiatric drugs with antidepressant and antipsychotic drugs being particularly implicated (table 1). In this chapter we focus on drug-induced QTc prolongation and torsade de pointes (TdP). QTc prolongation is a marker for the occurrence of TdP, a polymorphic ventricular arrhythmia. There are several reasons for this focus: • TdP is a serious side effect. It is associated with a range of clinical mani- festations including palpitations, syncope and sudden death. The overall mortality of TdP is between 10 and 17% (Salle et al 1985; Fung et al 2000). • QTc prolongation and TdP occur with many drugs and so the phenomenon has relevance to a wide range of patients as well as to clinicians practising in different specialities. • Genetic factors are relevant to drug-induced QTc prolongation and TdP. With regard to the last point, several cytochrome enzymes that metabolise QTc prolonging drugs display genetic polymorphisms. These can make individuals more susceptible to develop QT prolongation/TdP particularly when drugs are co-prescribed with the potential for pharmacokinetic interactions. In addition, a small minority of patients with drug induced QTc prolongation have a genetic predisposition in the form of a mutation in one of the genes that code for potassium channels involved in cardiac repolarisation. However this must be put into context, as at present the majority of patients with drug induced QTc prolongation do not have an indentifiable genetic vulnerability. ___________________________________________ * Peter M. Haddad, Cromwell House Community Mental Health Centre, Bolton, Salford & Trafford Mental Health NHS Trust, Manchester, M30 OGT, UK Cherry Lewin, Cromwell House Community Mental Health Centre, Bolton, Salford & Trafford Mental Health NHS Trust, Manchester, M30 OGT, UK 515 516 C. LEWIN ET AL. Table 1. Examples of cardiac side effects caused by psychiatric drugs Cardiac side Examples of causal drug Mechanism effect Postural • Dosulepin (tricyclic Blockage of hypotension antidepressant) adrenergic • Chlorpromazine (alpha-1) receptors (conventional antipsychotic) • Quetiapine (atypical antipsychotic) Hypertension • Venlafaxine (antidepressant: Noradrenergic serotonin and noradrenalin stimulation reuptake blocker, SNRI) QTc • Thioridazine (conventional Blockade of cardiac prolongation antipsychotic) potassium channels and/or TdP • Ziprasidone (atypical antipsychotic) • Lithium (mood stabiliser) Cardiomyopathy • Clozapine (atypical Hypersensitivity? antipsychotic) Myocarditis • Clozapine (atypical Hypersensitivity? antipsychotic) Tachycardia • Clozapine (atypical Antimuscarinic antipsychotic) blockade • Dosulepin (tricyclic antidepressant) 2. QTc PROLONGATION The QT interval on the electrocardiogram (ECG) is the time from the onset of ventricular depolarisation to completion of repolarisation, that is it reflects the duration of individual action potentials in the cardiac myocytes. The QT interval shortens with increasing heart rate and correcting for this variation gives the QTc or rate-corrected value. There are various formulae that can be used to calculate this correction and opinion is divided as to which is the most accurate. Bazett’s correction (QTc = QT/RR ½) is the most commonly used, but has the disadvantage of tending to overestimate the QTc at higher heart rates, and conversely to underestimate the QTc when applied to drugs (e.g. beta-blockers) which cause slowing of the heart rate. The Fridericia formula (QTc = QT/RR TdP 517 1/3) is less sensitive to this effect. Over or under correction is a disadvantage of all universal correction formulae when the heart rate extends beyond a narrow physiological range. The most reliable method of correction is to devise an individual formula for each individual, but this is expensive and requires large numbers of ECGs from each person. There is no evidence that any particular method is a better predictor of sudden death (de Bruyne et al.1999). The QT interval varies with gender (females have longer QT intervals) (Stramba-Badiale et al.1997) and time of day (it increases during sleep). It increases after a meal (Nagy et al.1997). Obesity has been associated with QTc prolongation (Carella et al.1996). The QTc interval also varies according to the positioning of ECG leads (Higham and Campbell1994) as it is subject to variation within the myocardium, a phenomenon known as QT dispersion. In healthy un-medicated subjects several studies have linked QTc prolongation to excess cardiovascular mortality (e.g. Schoeten et al 1991, Algra et al 1991) though other studies have failed to demonstrate such a link (Goldberg et al 1991). The marked variability between individuals makes it difficult to strictly define normal from abnormal QTc values. In 1997 the Committee for Proprietary Medicinal Products (CPMP) published a report on the assessment of QT interval prolongation by non-cardiovascular drugs. This used Bazett’s correction to suggest normal, borderline and prolonged values for both males and females (table 2). It is important to emphasise that there is no direct relationship between QTc interval and arrhythmic risk; raised QTc is simply a marker for increased risk. Table 2. Normal, borderline and prolonged QTc values (Bazett corrected; in the absence of any drug or disease) suggested by the Committee For Proprietary Medicinal Products (1997) Normal Borderline Prolonged msec msec msec Males <430 431 - 450 >450 Females <450 451 - 470 >470 3.TORSADE DE POINTES First described in the mid1960s, Torsade de Pointes, literally ‘twisting of the points’, is a polymorphic ventricular arrythmia that can progress to ventricular fibrillation and sudden death. The ‘twisting’ refers to the movement of QRS complexes around the isoelectric line of the ECG trace. Any delay in completing the repolarisation phase appears to allow the development of spontaneous depolarisations of non-pacemaker myocytes, so-called early after- de-polarisations. The occurrence of early after-depolarisations in combination with increased heterogeneity of cardiac repolarisation appears to act as a trigger for TdP. The relationship between increasing QT interval and risk of arrythmia 518 C. LEWIN ET AL. however is not linear, and some drugs (e.g. Amiodarone) cause QTc prolongation but rarely cause TdP. TdP can be asymptomatic or present with a variety of symptoms including palpitations. When TdP is prolonged symptoms arise from impaired cerebral circulation and include dizziness, syncope and seizures. In about 20% of cases TdP progresses to ventricular fibrillation and often sudden death will result (Salle et al 1985). The overall mortality of TdP is between 10 and 17% (Salle et al 1985; Fung et al 2000). 4. DRUGS ASSOCIATED WITH QTc PROLONGATION AND TdP When first described TdP was regarded as a side effect of cardiac drugs alone, or as being due to congenital long QT syndrome (see next section). It is now recognised that TdP can occur with a wide range of drugs including psycho-tropic and non-psychotropic drugs (Table 3). Among psychiatric drugs most attention has focused on antipsychotics, though other drugs can cause QTc prolongation including tricyclic antidepressants (TCAs), lithium and chloral hydrate (Haverkamp et al 2000). Selective serotonin reuptake inhibitors (SSRIs) have been studied and although occasional cases of QTc prolongation have been recorded they are generally felt to be less arrhythmogenic than the TCAs, even in overdose. A case TdP was recorded in a patient on citalopram (Meuleman et al 2001). In 1988 prenylamine, an antianginal drug, became the first drug to be withdrawn from the market because of concerns about is ability to cause QTc prolongation and TdP. Since that time at least 8 other drugs have been withdrawn from various markets for this reason. These include terodiline, terfenadine, astemizole, grepafloxacin, cisapride, levacetylmethadol and two antipsychotics, sertindole and droperidol. Identical concerns have led to prescribing restriction being introduced for many drugs including the antipsychotics pimozide and thioridazine. Prior to licensing, various drugs have had their development abandoned due to QTc concerns. Assessment of the proarrhythmic risk of drugs is now an important part of drug development and regulatory approval. TdP 519 Table 3. Examples of drugs associated with QTc prolongation and /or TdP (data from Haverkamp et al (2000) and FDA (2000): reproduced in modified form from Haddad and Anderson (2002) with permission) Antiarrhythmic Drugs Class 1a Disopyramide Procainamide Quinidine Class 3 Amiodarone Bretylium Dofetlidine Sotalol Antihistamines Astemizole Terfenadine (withdrawn) Antimicrobials and Antimalarials Fluoroquinolone antibiotics Grepafloxacin (withdrawn) Levofloxacin Sparfloxacine Macrolide antibiotics Clarithromycin Erythromycin Imidazole antifungals Ketoconazole Antimalarials Chloroquine Halofantrine Quinine Miscellaneous antimicrobials Co-trimoxazole Spiramycine Pentamidine Calcium Channel Bockers Prenylamine (withdrawn) Terodiline (withdrawn) Miscellaneous Non-Psychotropics Cisapride (withdrawn) Probucol Tricyclic and Related Antidepressants Amitriptyline Clomipramine Desipramine 520 C. LEWIN ET AL. Doxepin Imipramine Maprotiline Nortriptyline Typical Antipsychotics Chlorpromazine Droperidol (withdrawn) Fluphenazine Haloperidol Mesoridazine Pimozide