QTc Prolongation and Psychotropic Medications: New Reviews

I’m always looking for updates about QTc prolongation and Torsades de Pointes associated with psychotropic drugs, especially antidepressants and antipsychotics. I’ve lost count of the number of times I’ve been called as a psychiatric consultant about judgment calls regarding the safety of starting or continuing antidepressants or antipsychotics in the context of abnormally long QTc intervals.

This looks like a very long post about cardiac conduction prolongation due to psychotropic medications mainly because of the abstracts below. You should not substitute the information in this blog post (or any other post for that matter) for health guidance from your personal physician.

In order to provide the safest medical care possible, it’s absolutely vital all physicians stay apprised of any good studies which contribute substantially to our knowledge base about how to assess and manage the risks incurred by treating patients with any drugs that might cause harm of any kind.

There are many articles out there about this issue; I’m only sharing a few I’ve recently discovered which taught me something new and which confirm what I’ve learned before about the medically safest way to provide treatment for depression and to reduce dangerous agitation due to delirium in hospitalized patients.

The paper by Beach et al and the one by Doyle and Rosenthal both require subscriptions to access. They both include background about the basic cardiophysiology of QT prolongation and how psychotropic medications can affect it. Furthermore, they contain information about the role which specific classes of psychotropic drugs, including but not limited to antipsychotics and antidepressants, play in potentially prolonging QT prolongation. There’s enough information in them to help guide the application of safe-prescribing principles to clinical practice to ensure patient safety. Of course, there is no substitute for a frank, transparent risk to benefit discussion with patients and families.

A few highlights worth mentioning:

  • QTc prolongation is not the same thing as Torsades de Pointes (TdP, a malignant arrhythmia occurring in the setting of a prolonged QTc interval). Despite the association between antipsychotics and QTc prolongation, “the risk for TdP and sudden cardiac death remains unclear” [2]. All antipsychotics prolong QTc to some degree, thioridazine carrying the greatest risk for both. Haloperidol has also been associated with both QTc prolongation and TdP. The intravenous form (IV) of haloperidol may carry a higher risk of QTc prolongation than the oral preparation. This is important to remember because the IV form may be preferentially used in critical care units for the management of dangerous agitation due to delirium, often because patients are intubated and cannot take oral medications. The FDA recommends cardiac monitoring for all patients receiving IV haloperidol.
  • The Food and Drug Administration (FDA) revised the statement about citalopram in March 2012 to say “citalopram is not recommended for use at doses >40mg per day.” Another revision was to change “contraindicated” to ” not recommended” for patients with long QT syndrome (LQTS). It’s recommended to discontinue citalopram in any patient with a QTc interval greater than 500ms. There are no QTc-related recommendations issued for other SSRIs, although there are a couple of case reports about QTc prolongation in patients who had been taking escitalopram [1, 2].
  • The risk for QTc prolongation is influenced by a number of other factors in addition to the psychotropic drug, including but not limited to the co-administration of other nonpsychiatric drugs known to be associated with QTc prolongation (the list is long and the reader is referred to the articles), female gender, age, genetic mutations, comorbid medical conditions, and electrolyte abnormalities, especially potassium and magnesium. Even grapefruit juice can interact with other drugs to prolong QTc.
  • If baseline QTc is longer than 500ms, the physician should probably refer the patient to a cardiologist.
  • While there is “very limited data” to suggest that QTc pr0longation in a patient with schizophrenia taking antipsychotic is at significant risk without other factors involved, off-label use of antipsychotics, especially in the demented elderly “can be dangerous” [2].
  • One new piece of information for me was a new method for assessing the risk for TdP. Usually, many physicians, including consulting psychiatrists, tend to rely on the automated QTc measurement on the patient’s electrocardiogram (ECG). There are a number of difficulties that can make this number less than fully dependable. A new method called the QT nomogram may avoid the pitfalls of the QTc interval. The web links below to the papers by Chan et al and Waring et al are to open access papers about this new development which requires further study [3, 4].

References:

1. Beach, S. R., C. M. Celano, et al. (2013). “QTc prolongation, torsades de pointes, and psychotropic medications.” Psychosomatics 54(1): 1-13.
BACKGROUND: Prolongation of the corrected QT (QTc) interval is a key issue for patients who receive psychotropic medications. Such patients may have baseline clinical risk factors for QTc prolongation, and many psychotropic medications may further prolong this interval. This has great clinical relevance, as QTc prolongation is linked with dangerous arrhythmias, especially torsades de pointes (TdP). METHODS: We summarize current literature regarding appropriate methods of calculating the QTc interval, the association of the QTc interval with TdP, and risk factors for QTc prolongation. We then review connections between psychiatric medications and QTc prolongation, with a specific focus on antidepressants and antipsychotics. RESULTS: QTc interval prolongation is an established, though imperfect, risk marker for TdP. There are no well-controlled studies that assess the risk of TdP associated with psychotropic agents. There are limited data that selective serotonin reuptake inhibitors (SSRIs) as a class are linked to QTc prolongation; citalopram appears more likely than others to induce this phenomenon. Among antipsychotics, thioridazine remains the agent most associated with QTc prolongation; intravenous haloperidol also appears to carry an increased risk. Of the atypical antipsychotics, ziprasidone appears most likely to prolong the QTc interval. CONCLUSIONS: The majority of patients in need of psychotropic medications display few risk factors for QTc prolongation and should be considered to be at low risk for TdP. The frequency of cardiac monitoring for patients receiving psychiatric medications should be individually determined, based on the prescribed agent(s) and additional risk factors for TdP.

2. Doyle, M., MD, and L. J. Rosenthal, MD (2013). “Psychotropic Medications, Associated QTc Prolongation, and Sudden Cardiac Death: A Review for Clinicians.” Psychiatric Annals 43(2): 58-65.
1. Describe the basic cardiophysiology of QT prolongation and how psychotropic medication can affect it.

2. Understand the role that each class of drugs plays in the potential of QT prolongation.

3. Apply the principles to clinical practice in order to assure patient safety.

Prolongation of QTC is an electrocardiographic finding indicating prolongation of cardiac repolarization, which increases the risk for torsades de pointes, a form of ventricular tachycardia that can lead to sudden cardiac death. Sudden cardiac death in the setting of antipsychotic treatment was first described in the 1960s with thioridazine; since that time, many other psychotropic medications have been associated with QTc prolongation. This article reviews the electrophysiology of the cardiac cycle and the mechanism of QTc prolongation. Each major class of psychotropic medications also is reviewed, focusing on its propensity to prolong QTc and association with torsades de pointes (TdP) and sudden cardiac death. Other risk factors for TdP are also discussed. Examination of the management and treatment of QTc prolongation and TdP aims to assist the clinician with an approach to patients receiving psychotropic medications.

3. Chan, A., G. K. Isbister, et al. (2007). “Drug-induced QT prolongation and torsades de pointes: evaluation of a QT nomogram.” QJM 100(10): 609-615.
Background: Although QT prolongation is associated with increased risk of torsade de pointes (TdP), the precise relationship is not well defined.Aim: To evaluate the performance of a QT nomogram in assessing the risk of TdP from QT–RR combinations.Design: Systematic review.Methods: We systematically searched MEDLINE/EMBASE for cases of drug-induced TdP. Controls were patients taking non-cardiotoxic drugs in overdose. Inclusion criteria were definite TdP, normal ECG before or after the event, association with a drug/toxin and QT–RR measurements available. The upper bound of a QT–RR cloud diagram developed from human preclinical studies was converted into a QT nomogram [QT vs. heart rate (HR)]. QT–HR combinations for TdP cases and controls were plotted with the QT nomogram, and curves corresponding to a QTc = 440 ms and QTc = 500 ms for comparison (Bazett’s correction).Results: We identified 129 cases of TdP. TdP cases occurred at lower HR values with longer QT intervals, with most cases occurring at HR 30–90 bpm. Controls were more evenly distributed, with HR 40–160 bpm. The sensitivity and specificity of the QT nomogram were 96.9% (95%CI 93.9–99.9) and 98.7% (95%CI 96.8–100), respectively. For Bazett QTc = 440 ms, sensitivity and specificity were 98.5% (95%CI 96.3–100) and 66.7% (95%CI 58.6–74.7), respectively, whereas for Bazett QTc =500 ms they were 93.8% (95%CI 89.6–98.0) and 97.2% (95%CI 94.3–100), respectively.Discussion: The QT nomogram is a clinically relevant risk assessment tool that accurately predicts arrhythmogenic risk for drug-induced QT prolongation. Further prospective evaluation of the nomogram is needed. http://qjmed.oxfordjournals.org/content/100/10/609.long

4. Waring, W. S., A. Graham, et al. (2010). “Evaluation of a QT nomogram for risk assessment after antidepressant overdose.” British journal of clinical pharmacology 70(6): 881-885.
AIMS: A QT-heart rate nomogram has recently been proposed as a means of identifying patients at risk of torsades de pointes after antidepressant overdose, based on published cases of drug-induced torsades de pointes. The present study sought to examine the performance of the nomogram in patients who ingest an antidepressant overdose but do not develop arrhythmia. METHODS: A retrospective case control study of patients presenting to hospital after overdose of citalopram, mirtazapine and venlafaxine was carried out. The primary outcome variable was QT higher than the nomogram, and was compared with occurrence of QT(c) (QT corrected by Bazett’s formula) greater than >/=440 ms and QT(c) >/=500 ms, with comparison between drugs. Data are expressed as proportions in each group with 95% confidence intervals. RESULTS: There were 858 electrocardiograms from 541 patients. QT was higher than the nomogram in 2.4% (1.4, 4.1%), whereas QT(c) was >/=440 ms in 23.1% (95% CI 19.8, 26.8%), and QT(c) was >/=500 ms in 1.1% (0.5, 2.5%). Citalopram overdose was more likely to be associated with QT higher than the nomogram compared with the other agents (difference 7.0%, 95% CI 2.9, 11.9%, P = 0.001) and more likely to be associated with QT(c) >/=440 ms (difference = 11.0%, 95% CI 2.6, 19.0%, P = 0.013). CONCLUSIONS: The QT nomogram was associated with a lower false positive rate than widely accepted QT(c) criteria, and allowed detection of different effects of individual drugs. The nomogram offers potential advantages over QT(c) criteria and merits further investigation in a clinical setting. Evaluation of a QT nomogram for risk assessment after antidepressant overdose

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Comments

  1. Been there! Hospitalized 2 yrs ago for prolonged QT syndrome and prior to surgical implantation of a defibrillator scheduled for the following day had the presence of mind to request an electrophysiology consult which resulted in psych meds being found as the culprit…..surgery averted. Funny how the med prescriber and pharmacist failed to mention this possibility. Thank heaven for the astute specialist who checked my med list thoroughly.

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