Antipsychotics, QTc Prolongation, and the Elderly


Reeja C. Menon, MD, Sreenath V. Nair, MD, Reji Attupurath, MD, Sunanda Muralee, MD, Rehan Aziz, MD, and Rajesh R. Tampi, MD, MS


Pages 18 - 24

Introduction Antipsychotic medications remain a viable therapeutic strategy with well-documented efficacy in a variety of geriatric psychiatric disorders, including behavioral disturbances (particularly agitation and aggression) in dementia and psychosis.1 They are among the most commonly utilized psychotropic drugs in this population, particularly among the 5-8% of individuals who are institutionalized.2 There is evidence that patients residing in nursing homes may receive antipsychotic medications for up to 17 of every 100 days.3 In an excellent review, Jeste and colleagues4 reviewed the use of antipsychotics in older patients with schizophrenia in three randomized, double-blind, placebo-controlled trials. They concluded that taken together, these trials offer support for the use of atypical antipsychotics in late-life schizophrenia. In a study conducted by Howanitz et al,5 chlorpromazine and clozapine were reported to produce similar levels of symptomatic benefit. In a larger study conducted by Kennedy et al,6 olanzapine was compared to haloperidol in older adults with schizophrenia and related disorders as part of a subanalysis of a previous study. Olanzapine produced significantly greater symptomatic benefits as compared to haloperidol, as well as fewer motor side effects. Jeste and colleagues7 conducted a prospective trial comparing olanzapine and risperidone in elderly patients with schizophrenia. In this study, similar improvements in symptoms were noted, with 59% of olanzapine-treated patients and 58% of risperidone-treated patients being considered treatment responders.7 Elderly patients with depression usually present with higher rates of psychotic symptoms as compared to their younger counterparts.8 The Epidemiologic Catchment Area (ECA) survey reported a range of psychosis from 16-23% in an older adult population.9 In addition, psychotic late-onset depression accounts for nearly 25-50% of admissions to inpatient geriatric psychiatry units.10 The presence of psychotic symptoms in depression appears to be a poor prognostic sign, as patients with these symptoms present with frequent recurrences and repeated hospitalizations.11 For psychotic depression, the recommended treatment is to use antipsychotics and antidepressants in combination as first-line agents.12 Two reviews also indicate that atypical antipsychotics have been used effectively in the treatment of bipolar disorder in late life.13,14 Anxiety disorders are the most prevalent of psychiatric disorders in the elderly.15 The ECA data indicate that the prevalence rates of anxiety disorders in the elderly range from 10.2-15%, which is higher than the rates seen in the adult population (8.3%). Although antidepressants and benzodiazepines form the mainstay of the pharmacological treatment of anxiety disorders in the elderly, antipsychotics are now being used in the treatment of anxiety disorders, especially those refractory to standard treatment.16,17 Both traditional and atypical antipsychotic medications have been shown to be effective in the treatment of psychiatric illness in older persons, with the latter having a better extrapyramidal side-effect profile. However, it is now clear that these atypical drugs come with certain side effects not seen in the typical class of drugs, namely the metabolic syndrome: hyperlipidemia, weight gain, hyperglycemia, and diabetes mellitus.18-20 The tolerability of antipsychotic medications in the elderly continues to generate a lot of interest; however, no adverse effect has been subject to more discussion in recent times than the reported association between increased mortality in patients with dementia and antipsychotic therapy.21 A black box warning to that effect has been assigned to the atypical antipsychotic medications.21 Although antipsychotics have been reported to cause death by several proposed mechanisms, the precise etiology of increased mortality in patients with dementia is an evolving area and remains a subject of intense debate and research. There are reports suggesting that history of stroke is a risk factor.22-24 Faced with a potentially fatal adverse effect of a medication class yet to be approved by the U.S. Food and Drug Administration (FDA) for dementia management, clinicians are very likely to underutilize an otherwise effective therapeutic intervention, underscoring the need for clear and evidenced-based risk stratification paradigms and treatment guidelines when using these medications. The introduction of ziprasidone and then withdrawal, the restricted labeling of some antipsychotic drugs, and the reported association between atypical antipsychotics and sudden death in patients with dementia21 have led to a renewed focus on the effects of these medications on the QT interval. Prolonged QT interval may be associated with dizziness, lightheadedness, palpitations, presyncope or syncope, and ventricular tachyarrhythmias including polymorphic ventricular tachycardia or torsades de pointes (TdP).25,26 While most cases of TdP resolve spontaneously, some may degenerate into ventricular fibrillation and sudden cardiac death if not treated promptly with cardiopulmonary support and cardioversion.25 First described in 1966,27-29 and thought to be limited to patients taking cardiac drugs and people with congenital long QT interval,28 TdP has since been documented with noncardiac medications including an antihistamine (terfenadine, which has been removed from the market) and antipsychotic medications.29,30 There are reports suggesting that current use of a noncardiac QTc-prolonging drug is associated with a 2.7 increase in adjusted odds ratio mortality versus nonusers.31 Electrophysiology of Action Potential, QT Prolongation, Torsades de Pointes, and Ventricular Fibrillation Ventricular myocardial action potential (AP) is the result of influx and outward flow of specific ions at unique times during the AP event.32 Myocardial negative resting membrane potential is a product of intracellular versus extracellular ratio of potassium ions.33 The sudden influx of sodium ions through the sodium fast channel is responsible for AP upstroke and coincides with ventricular depolarization and the QRS complex of the electrocardiogram (EKG).34 The potassium channel acts during the repolarization phase of AP and allows potassium to leave the intracellular space, leading to a more negative, and thus intracellular, repolarization. The QT interval stretches from the start of the QRS complex to the end of the T wave.35 It corresponds to periods of ventricular depolarization (QRS) and ventricular repolarization (ST segment and T wave).36 If the potassium rectifier channel is impeded, as is the case with antipsychotic medication, or to a lesser extent by a tricyclic antidepressant, the cell is “stuck” in a depolarized state, prolonging the QT interval.32,35 Although the mechanism of QT interval prolongation by antipsychotic medications is well known, many aspects of this potentially fatal adverse event remain unclear.26 The most accurate calculation of the QT interval (the use of serial EKGs or signal-averaged EKGs to monitor the QT interval) and the standard recommendations for managing a patient who develops or is at risk of a polymorphic ventricular arrhythmia that can progress to ventricular fibrillation and sudden death in the general adult population32,35 have not been well delineated. The QT interval is regarded as a surrogate marker for TdP.32 Understanding the background for QT interval prolongation can aid clinicians in making decisions regarding choice of psychotropic medications. QT interval varies inversely with heart rate and can be adjusted for heart rate by many different formulas. The most commonly used formula is the one described by Bazett, in which the QTc (corrected QT interval) is equal to the QT interval divided by the square root of the R-R35,37 interval measured in seconds. However, the Fridericia formula, which uses the cube root of the R-R, may provide a more accurate correction of the QT interval.35,38,39 One criticism of the Bazett formula is that it overcorrects for bradycardia, leading to a higher estimation of the QT interval (yields erroneously short QTc intervals).40 Another problem with the QT interval assessment is that there are no rigid guidelines for normal values.32,36 It is generally accepted that women have slightly longer average QT intervals than men.41 QTc values above 470 milliseconds are in the prolonged range for either sex.42 It is also important to note that the QT interval fluctuates throughout the day by as much as 76 (+/- 19) milliseconds.43 Factors Affecting QTc Interval, Cardiovascular Changes of Aging, and Risk Stratification for Torsades de Pointes Several factors affect QTc interval (Table I). Cardiac disease and electrolyte abnormalities can predispose a patient to prolonged QTc interval.35,36 Females are particularly at risk, and approximately 70% of the cases of TdP occur in women.44 The elderly are at risk because they are susceptible to polypharmacy, cardiovascular disease (CVD), and have decreased metabolism of drugs.32 In addition, 5-10% of European Americans have decreased CYP2D6 activity,45 leading to increased antipsychotic drug levels. Electrolyte abnormalities, particularly hypokalemia and hypomagnesemia, can lead to TdP.26,46,47 Antipsychotic medications have variable propensity for QTc interval prolongation (Table II). One study showed an average increase in the QTc of 4.7 milliseconds with haloperidol and up to 35.6 milliseconds with thioridazine.48 Subjects were young males with a baseline QTc interval of less than 450 milliseconds.48 The study also showed that despite the low average changes in QTc, there were individuals with large changes.48 For example, 4% of patients taking haloperidol had an increase in QTc of greater than 60 milliseconds. Although thioridazine has the highest risk of causing TdP and sudden deaths, there are reports suggesting that other antipsychotic medications such as pimozide, sertindole, droperidol, and haloperidol may cause increased mortality through QTc interval prolongation.49 In a study of 495 psychiatric patients, Reilly et al50 found that 8% of those taking an antipsychotic medication, 11% of those taking a tricyclic antidepressant, and 15% of those taking both had prolonged QTc intervals, with a normal QTc in their study defined as 456 milliseconds or less. QTc prolongation is also associated with increased age, antipsychotic dose, and female gender.51 Although a prolonged QTc alone is often asymptomatic, it can lead to the fatal arrhythmia TdP.25 Bednar and colleagues52 reported that the total number of cases recorded in the literature with TdP was nine when QTc was less than 500 milliseconds, and 107 when QTc was greater than 500 milliseconds. Older patients are at increased risk for QTc interval prolongation and sudden cardiac death.51 To the best of our knowledge, no study has been undertaken to specifically assess the propensity for this risk. Studies that have investigated antipsychotic-induced QTc interval prolongation by their very exclusionary criteria have selection bias against the elderly population in general and patients with dementia in particular.48,49 A myriad of cardiovascular changes occurring with aging have been well documented.53 Physiologic and structural changes occurring in the cardiovascular system of the elderly limit the performance of physical activities, decrease cardiac functional capacity, and impair the capacity to adapt to a variety of stresses, particularly CVD.53 Impedance to left ventricular ejection and increased arterial systolic pressure engendered by aortic and large-artery thickness result in increased afterload in the elderly, which in turn stimulates left ventricular hypertrophy.54 Reduced chronotropic and ionotropic reactivity to sympathetic stimulation, increased duration of myocardial contraction and relaxation times and diastolic dysfunction have been described in the elderly55; also, loss of vascular distensibility results in dampening of baroceptor reactivity to changing blood volume accounting for the more than 18% orthostasis-induced fall rate in the elderly.56 Arrhythmias in the geriatric population constitute a large proportion of hospitalizations, consultations, and emergencies.57 It has been estimated that about half of elderly cohorts have abnormal resting EKG.58 These include PR and QT interval prolongation, nonspecific ST-segment and T-wave changes, intraventricular conduction defects, and QRS complex reduction.59 There is evidence suggesting that QT dispersion predicts mortality in the geriatric population.60 Taken together, these multiple changes in the geriatric cardiovascular function potentially portend two important premises: (1) unstable myocardial rhythms; and (2) reduced cardiovascular reserve; arrhythmias are not only more common, they are more clinically significant when they occur. It has been suggested that 320 sudden cardiac deaths per year are caused by drug-induced QTc interval prolongation in the Netherlands; this figure amounts to 9000 and 6000 deaths in Europe and in the United States, respectively, by extrapolation.31 Most of the covariates of sudden mortality, including cardiovascular ischemia, cerebrovascular disease, hypertension, heart failure, diabetes, and hypercholesterolemia, are more common in the geriatric population, suggesting possible synergistic or cumulative causality.31 Two recent articles have focused their attention on the cardiac safety of psychotropic medications.61,62 In the study by Ray et al,61 the authors calculated the adjusted incidence of sudden cardiac death among current users of antipsychotic drugs in a retrospective cohort study of Medicaid enrollees in the state of Tennessee. In their primary analysis, they included 44,218 and 46,089 baseline users of single typical and atypical drugs and 186,600 matched nonusers of antipsychotic drugs. They calculated that current users of typical and of atypical antipsychotic drugs had higher rates of sudden cardiac death than did nonusers of antipsychotic drugs, with adjusted incidence rate ratios of 1.99 (95% confidence interval [CI], 1.68-2.34) and 2.26 (95% CI, 1.88-2.72), respectively. The incidence rate ratio for users of atypical antipsychotic drugs as compared with users of typical antipsychotic drugs was 1.14 (95% CI, 0.93-1.39). The authors also found that former users of antipsychotic drugs had no significantly increased risk (incidence rate ratio, 1.13; 95% CI, 0.98-1.30). For both classes of drugs, the risk for current users increased significantly with an increasing dose. Among users of typical antipsychotic drugs, the incidence rate ratios increased from 1.31 (95% CI, 0.97-1.77) for those taking low doses to 2.42 (95% CI, 1.91-3.06) for those taking high doses (P Recommendations for Antipsychotic Use in Older Persons With QTc Prolongation Given the role of antipsychotics in the management of psychiatric disorders in older persons and the increased risk for QTc interval prolongation, the importance of developing risk stratification and treatment guidelines cannot be overemphasized. A. Mild Risk for QTc Interval Prolongation (Patients Who Are in Relatively Good Physical Health) a) No current cardiovascular symptom or disease, and no history of severe CVD b) Normal EKG with pretreatment QTc interval less than 450 milliseconds c) Absence of other diseases that are known to predispose to QTc interval prolongation (Table I) d) No concurrent cardiac or noncardiac medication that could increase QTc interval • For these patients, a baseline EKG prior to initiation of antipsychotic therapy and annual reassessment of QTc interval prolongation risk will suffice. • Regarding choice of antipsychotic medication, those known to have lower QTc interval prolongation are generally preferred. • Ziprasidone may be used in these patients, but only as a third-line option and with regular EKG monitoring. B. Moderate Risk for QTc Interval Prolongation (Patients Who Have a Few Risk Factors in Whom Risk-Benefit Analysis Favors Benefit) a) Current stable cardiovascular function: no current cardiovascular symptoms or disease but with significant past history of CVD b) EKG abnormalities from past cardiovascular events that have little or no current clinical significance (eg, mild ST segments and T-wave changes due to past myocardial infarction) c) Presence of noncardiac diseases that could impact QTc interval, or two or more diseases listed in Table I d) Concurrent use of at least one noncardiac medication known to prolong QTc interval e) History of stroke with residual neurological deficits f) a, b, c, and d or mildly elevated QTc interval of 450-470 milliseconds • In these patients with moderate risk of QTc prolongation, alternative psychotropic medications should be considered (eg, mood stabilizers or antidepressants). • Cardiology consult is recommended for joint management. • Ziprasidone and all low- and mid-potency traditional antipsychotic medications are not recommended. • Prior to initiating antipsychotic medication, baseline EKG, optimum management of preexisting diseases, and alternatives to noncardiac medications capable of prolonging QTc interval should considered. • A much lower dose and very slow titration of antipsychotic medications is recommended. • Serial EKG’s recordings may be helpful to adjust for daily variations in the QTc interval. In patients with moderate risk, any upward trending of QTc interval prolongation is an indication to discontinue antipsychotic therapy. C. High Risk for QTc Interval Prolongation a) Presence of active cardiac disease or symptoms b) Presence of multiple other risk factors listed in Table I c) Moderate-to-severe EKG abnormalities d) Frail elderly In these patients, there is substantial risk of significant QTc interval prolongation that may or may not result in an untoward cardiac event. • Antipsychotic therapy is not recommended if one or more of these factors are present. • Nonpharmacologic and psychotropics other than antipsychotic medications may be the optimum approach in these patients. • Haloperidol and olanzapine are less likely to increase the QTc by a large amount and are thus preferred in these patients if antipsychotic therapy is indicated. A major concern when using a high-potency dopamine-blocking drug such as haloperidol in older persons is the risk of developing tardive dyskinesia (TD). Patients over 40 years of age are three times more likely to develop TD.63-65 The development of extrapyramidal side effects such as akathisia, dystonia, or parkinsonism is a major risk factor for the development of TD.66,67 Conclusion Antipsychotic medications are commonly used in the management of psychiatric disorders in the elderly. Given the increasing frequency of their use in older patients and their propensity to cause QTc interval prolongation, an understanding of their cardiac safety is of utmost importance. Use of these medications without any risk stratification or close monitoring will result in catastrophic consequences (ie, sudden death from ventricular fibrillation). Based on current evidence, it is clear that QTc prolongation is associated with all of the antipsychotic medications. The risk of significant and dangerous QTc prolongation is higher in elderly patients with preexisting cardiac disease and metabolic abnormalities. Close monitoring, correction of underlying metabolic and electrolyte abnormalities, and avoidance of concurrent use of drugs known to prolong the QTc interval are essential in these high-risk patients. The use of antipsychotics with lower risk of QTc prolongation will also prevent the development of fatal arrythmias. Until the development of newer and safer medications to treat behavioral disturbances and psychoses in the elderly, the careful selection and dosing of available medications is the only viable alternative left to clinicians. To better clarify the precise liability of QTc interval prolongation by different antipsychotic medications in older persons, a prospective, single-blinded comparative study could be designed with serial EKG monitoring of antipsychotic-naïve elderly patients who begin therapy versus a control group that is not taking antipsychotic medications. The authors would like to thank Solomon Williams, MD, Department of Psychiatry, Texas A & M University, for his help with the development of this article. The authors report no relevant financial relationships. Dr. Menon, Dr. Nair, and Dr. Attupurath are in private practice; and Dr. Muralee, Dr. Aziz, and Dr. Tampi are from the Department of Psychiatry, Yale University School of Medicine, New Haven, CT.

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