Current Drug Safety, 2010, 5, 97-104 97 1574-8863/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd. QT Alterations in Psychopharmacology: Proven Candidates and Suspects Paulino Antonio Alvarez *,1 and Jaime Pahissa 2 1 Department of Internal Medicine, CEMIC, Buenos Aires, Argentina 2 Department of Psychiatry, CEMIC, Buenos Aires, Argentina Abstract: Psychotropics are among the most common causes of drug induced acquired long QT syndrome. Blockage of Human ether-a- go-go-related gene (HERG) potassium channel by psychoactive drugs appears to be related to this adverse effect. Antipsychotics such as haloperidol, thioridazine, sertindole, pimozide, risperidone, ziprasidone, quetiapine, olanzapine and antidepressants such as amitriptyline, imipramine, doxepin, trazadone, fluoxetine depress the delayed rectifier potassium current (Ikr) in a dose dependent manner in experimental models. The frequency of QTc prolongation (more than 456ms) in psychiatric patients is estimated to be 8%. Age over 65 years, tricyclic antidepressants (TCA), thioridazine, droperidol, olanzapine, and higher antipsychotic doses were predictors of significant QTc prolongation. In large epidemiological controlled studies a dose dependent increased risk of sudden death has been identified in current users of antipsychotics (conventional and atypical) and of TCA. Thioridazine and haloperidol shared a similar relative risk of SCD. Lower doses of risperidone had a higher relative risk than haloperidol for cardiac arrest and ventricular arrhythmia. No increased risk was identified in current users of selective serotonin reuptake inhibitors (SSRI). Cases of TdP have been reported with thioridazine, haloperidol, ziprazidone, olanzapine and TCA. Evidence of QTc prolongation with sertindole is significant and this drug has not been approved by the Food and Drugs Administration (FDA). A large trial is ongoing to evaluate the cardiac risk profile of ziprazidone and olanzapine. Selective serotonin reuptake inhibitors have been associated with QTc prolongation but no cases of TdP have been reported with the use of these agents. There are no reported cases of lithium induced TdP. Risk factors for drug induced LQT syndrome and TdP include: female gender, concomitant cardiovascular disease, substance abuse, drug interactions, bradychardia, electrolyte disorders, anorexia nervosa, and congenital Long QT syndrome. Careful selection of the psychotropic and identification of patient´s risk factors for QTc prolongation is applicable in current clinical practice. Keywords: Psychotropics, QTc prolongation, torsades de pointes, antipsychotics, antidepressants. INTRODUCTION Since the 1950s drugs with demonstrated efficacy in a broad range of severe psychiatric disorders became available leading to the development of psychopharmacology. Psychoactive drugs have been associated with acquired Long QT (LQT) syndrome and Torsades de Pointes (TdP) [1]. Usually the interval between the marketing of these drugs and the recognition of this association is measured in years [2]. One of the reasons is that the number of spontaneously submitted adverse drug reaction reports depends on cumulative patient exposure [3]. The prevalence of mental illness is increasing and by 2020 major depression is expected to be second only to heart disease [4]. The lifetime incidence of major depressive disorder in the United States is estimated to be more than 12% in men and 20% in women [5]. The interaction of depressive disorders and chronic disorders (e.g. cardiovascular disease) is being increasingly recognized. For example depression has been associated with increased prevalence of risk factors for coronary artery disease, increased occurrence of stroke and myocardial infarction [6]. Aging is a global phenomenon, that has unprecedented and profound implications [7]. Geriatric patients are at increased risk of adverse drug reactions because of polypharmacy and multiple comorbid conditions [8]. In the United States, 12.5 million patients 65 years of age or older are hospitalized each year. Delirium complicates approximately 20% of the hospital stays [9]. Antipsychotics are usually used to control agitation [10]. *Address correspondence to this author at the Department of Internal Medicine, CEMIC, Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”. Las Heras 2900 - (C1425ASS), Buenos Aires, Argentina; E-mail: palvarez@cemic.edu.ar Given the above it’s not difficult to understand why psychotropics are among the most common QT prolonging drugs prescribed [11]. Trying to prevent TdP has become a major public health problem and has important regulatory implications [12]. THE BIOLOGICAL BASIS OF PSYCHOTROPIC INDUCED QTC INTERVAL PROLONGATION Cardiac K + -selective currents are responsible for setting the resting membrane potential and repolarization. Central to our discussion is the rapid component of the delayed rectifier current (Ik r ). Ik r is specifically blocked by methanesulfonilide antiarrhythmic agents (e.g. Dofetilide). Human ether-a-go-go- related gene (HERG), appears to be the molecular basis of this current [13]. Since blockade of Ikr is a known mechanism for drug- induced cardiac arrhythmias, the finding that HERG encodes Ik r channels provides a mechanistic link between certain forms of inherited and acquired LQT [14]. Almost all the drugs that prolong the QT interval block HERG potassium channel [15]. Using patch clamp electrophysiology and radioligand binding assays Kongsamut S. et al. analyzed the effect on Ik r and the affinities for HERG potassium channels of several antipsychotics [16]. Sertindole had the highest affinity followed by pimozide, risperidone, ziprasidone and thioridazine. Olanzapine and quetiapine had the lowest affinity [16]. Thioridazine like pimozide and sertindole display similar affinities (less that 10 fold difference) for HERG and dopamine (D 2 ) or serotonin (5-HT 2A ) (target) receptors. This may account for a low therapeutic index [16]. All the antipsychotics tested depress the Ik r current in a dose dependent manner. The IC 50 values (95% confidence limits) were sertindole, 2.7nM (2.1-3.5nM); pimozide, 18nM (14-22nM); risperidone, 167nM (128-215nM); ziprasidone, 169nM (133- 212nM); thioridazine191 nM (162-215); quetiapine 5765nM (4688- 7079) and olanzapine 6013nM (5140-7030). The authors compared