Prescribed medications can increase the risk of sudden cardiac death, one of the single most common causes of death in industrialized countries. Thus, an important strategy for prevention is identifying medications that increase the risk of sudden cardiac death and using this information to guide clinical practice. The prevailing approach to identification of high-risk medications has been study of electrophysiologic markers of arrhythmia risk and case reports of torsade de pointes. However, while these methods can identify extreme risks, they often are inconclusive. We have utilized the Tennessee Medicaid automated database to identify important, yet unexpected, increased risks of sudden cardiac death for several commonly prescribed medications, including oral erythromycin, cyclic antidepressants, and antipsychotics. We propose to utilize this methodology to study other medications taken by more than 11 million patients in the U.S. with a strong signal suggesting increased risk for sudden cardiac death, but inconclusive evidence: contemporary antidepressants, methadone, and concurrent use of antipsychotics with drugs likely to inhibit their metabolism. Electrophysiologic studies and case reports of torsade de pointes suggest four specific widely used antidepressants--fluoxetine, citalopram, escitalopram, and trazodone--may increase risk of sudden cardiac death. The m-opioid agonist methadone, now most commonly used for chronic pain, prolongs cardiac repolarization and can cause torsade de pointes, suggesting it may increase the risk of sudden cardiac death. Several medications commonly prescribed with antipsychotics, such as fluoxetine and ciprofloxacin, markedly inhibit antipsychotic metabolism, which may increase antipsychotic effective dose and thus the risk of sudden cardiac death. To better define the cardiac risks of these widely used drugs, we propose a series of controlled epidemiologic studies in Tennessee Medicaid with three specific aims: 1. Test the hypothesis that sudden cardiac death risk varies for individual antidepressants and that four drugs--fluoxetine, citalopram, escitalopram, and trazodone--increase risk. 2. Test the hypothesis that in patients treated for chronic pain, the risk of sudden cardiac death in methadone users is greater than that for comparable opioid analgesics. 3. Test the hypothesis that concurrent antipsychotic use with strong inhibitors of their metabolism increases the risk of sudden cardiac death relative to such use without metabolic inhibitors. The novel quantitative data these studies will provide are critical for optimal clinical practice, as they will enable safer drug choices, particularly for patients with high baseline cardiovascular risk. PUBLIC HEALTH RELEVANCE: We will quantify risk of sudden cardiac death, a leading cause of death, for specific contemporary antidepressants, methadone, and antipsychotics with metabolic inhibitors. The resulting data will enable clinicians to make safer drug choices, particularly for patients with high baseline cardiovascular risk.