QTc Prolongation and Psychotropics- Management of Prolonged QTc interval in Psychiatry
Psychotropic drugs are known to be associated with a prolonged QTc interval with differing risk profiles. As psychotropic drugs prolong cardiac repolarization, they increase the risk of Torsades de Pointes (TdP).
Heart rate corrected QT interval (QTc) on the ECG is the most widely used and accepted marker to screen for the risk of Torsades de Pointes.
There are no currently clear guidelines with regards to prescribing, and monitoring of psychotropic medications in the context of QTc and this article is meant to provide some guidance with regards to the use of psychotropic medications and QTc interval prolongation.
We cover key points from [Xiong G et al., 2020] and [Funk M et al., 2020] to assist clinicians in prescribing medications with lower QTc prolongation risk, monitoring requirements and managing QTc prolongation.
THE QTc INTERVAL
The QT interval is defined as the distance from the beginning of the QRS complex to the end of the T wave.
When using Bazett’s or Fridericia’s formulae to correct for heart rate, the RR interval from the preceding cycle length is used.
The duration of the QT interval is dependent on heart rate, and the QT interval needs to be “corrected” giving a corrected QT (QTc) for heart rate to make it more consistent and clinically meaningful.
There are two main methods for calculating QTc.
QTcB = QT / √RR
- The Bazett’s formula overestimates the QTc interval at high heart rates (>60 bpm) and underestimates the QTc interval in bradycardia (<60 bpm), and is likely to be the least reliable method of correction.
- This method is used in most ECG machines.
2. Fridericia’s formula:(www.ich.org)
QTcF = QT / ∛RR
This formula uses the cube root of heart rate and is less influenced by extremes of heart rate.
There are other less used methods such as Hodges and Framingham, which are used less frequently.
PATHOPHYSIOLOGY OF PROLONGED QTc INTERVAL
The QT interval is a measure of the combination of cardiac depolarisation and repolarisation. [Postema P & Wilde A, 2014]
Resting potential is maintained by the sodium-potassium pump.
Cardiac depolarisation (QRS interval) :
- Dependent on fast inward sodium ions (NaI) through the cardiac sodium channels.
Cardiac Repolarisation (JT/QT interval) :
- Determined by net efflux of outward potassium ions (Ki).
The majority of drugs associated with QTc interval prolongation and TdP are linked to pharmacological blockade of hERG (human-Ether-a-go-Related Gene) potassium channels which produce a repolarizing current termed the delayed rectifier current (IKr) resulting in longer action potential and therefore a delayed QT interval.
TORSADES DE POINTES
An abnormally long QT increases the risk of Torsades de Pointes (TdP).
A QTc greater than 500 msec is associated with a twofold to a threefold higher risk for TdP, and each 10-msec increase contributes to approximately a 5% to 7% exponential increase in risk. [Li M & Ramos L, 2017]
Torsades de Pointes (twisting of points) is a rare form of polymorphic ventricular tachycardia characterised by twisting of QRS complexes along the isoelectric line.
Torsades de Pointes may progress to a fatal ventricular arrhythmia.
Clinical features of Torsades de Pointes are:
- Chest pain
- Shortness of breath
The Rotterdam prospective population-based cohort study showed that a prolonged QTc interval was associated with a three-fold (eight-fold for > 68 years of age) increased risk of sudden cardiac death over a 6-7 year follow-up period. [Straus S et al., 2006]
RISK FACTORS FOR QTc PROLONGATION
- Age > 65 years
- Female sex
- Congenital long-QT syndrome
- Sudden cardiac death in first-degree family member
- Structural heart disease (e.g., coronary artery disease, congestive heart failure)
- Underlying arrhythmia
- Personal history of unexplained syncope
- Two or more QTc-prolonging agents
- Pharmacological plan for drug-interactions and drug toxicity
- Rapid intravenous infusion of QTc interval prolonging drugs
- Severe acute systemic illness
- Inadequate dose adjustment of hepatically metabolised drugs in patients with hepatic sclerosis
- Inadequate dose adjustment of renally eliminated drugs in patients with acute kidney or intercurrent kidney disease
- Risk or presence of hypokalaemia, hypomagnesaemia or hypocalcaemia
ANTIPSYCHOTICS AND QTc INTERVAL
Both typical and atypical psychotic medications have been associated with QTc interval prolongation and sudden cardiac death.
As many as 75% of TdP cases occur at therapeutic doses of antipsychotic medications.
Amongst typical antipsychotics, the highest risk of QTc interval prolongation is with thioridazine greatest risk of QTc interval prolongation (28-37 msec), compared to oral haloperidol (4-9 msec).
Amongst Second-generation antipsychotics (SGAs), Ziprasidone has the highest risk with a potential to add 15.9 ms to the baseline QTc interval.
The route of administration also influences QT interval with IV haloperidol and droperidol both carrying FDA boxed warnings for QTc prolongation.
The U.S. FDA accordingly recommends placing any patient prescribed intravenous haloperidol on a cardiac monitor given the high risk of QTc prolongation (16 msec).
A systematic review of studies evaluating droperidol’s effect on QTc demonstrated that droperidol is associated with about the same risk of QTc prolongation as other anti-agitation medications at intramuscular or intravenous doses of up to 10 mg.[Perkins J et al., 2015]
Cardiac monitoring is essential in the setting of intravenous haloperidol use.
ANTIDEPRESSANTS AND QTc INTERVAL
In August 2011, the FDA issued a warning for QTc prolongation with Citalopram.
Citalopram was associated with a mean prolongation of 4.5 msec at 10 mg, 8.5 msec doses of 20 mg, 10.7 msec at 30 mg and 18.5 msec at doses of 60 mg.
Escitalopram is associated with a mean prolongation of 4.5 ms with 10 mg/day dose and 10.7 ms with 30mg/day dose. However, a large meta-analysis of approximately 3300 patients showed a mean prolongation of 3.5 msec. [Thase M et al., 2013]
The evidence to date suggests that citalopram (which increases QTc by about 10–20 msec) and escitalopram (which increases QTc by about 5–11 msec) carry the highest risk of QTc prolongation among second-generation antidepressants (e.g., selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors), while most other antidepressants have negligible effects on QTc. [Xiong G et al., 2020]
When applying these results to real-life clinical practice, it is essential to consider that QTc interval changes in the range of 10-20ms, as found in the citalopram studies, are below the limits of detection on an individual ECG and may only yield a signal in large samples. QTc interval changes in the range of 30- 60ms would be considered potential signals; changes >60ms should be considered unusual and signals of concern. Hence, though the QTc interval changes with citalopram separate out from the other SSRIs, the clinical impact in isolation of other risk factors is insignificant.
It is also important to keep in mind that, for some patients, the risk of QTc interval prolongation with 60mg of citalopram is not as significant as the risk of psychiatric decompensation with a lower dose. There is evidence to suggest that the FDA warning has not reduced all-cause or cardiac mortality, but has led to increased rates of psychiatric hospitalizations for patients whose dose was reduced reflexively. Another study found that patients who had their dose of citalopram reflexively reduced were more likely to be prescribed sedatives or anxiolytics and had higher healthcare utilization. These studies highlight the importance of comprehensively considering all factors contributing to the risk-benefit ratio when prescribing “at-risk” medications. [Funk M et al., 2020]
OTHER PSYCHOTROPICS and QTc INTERVAL
- Methadone shows a dose-dependent QTc prolongation (oral methadone) with an approximately 10 msec increase in QTc for every 50 mg daily dose increase.
- Lithium within a therapeutic dose shows no significant association with QTc interval prolongation.
- Lithium concentrations > 1.2 mmol, however, can markedly prolong the QTc interval.
- Lamotrigine, topiramate and valproate do not show significant QTc interval prolongation.
Stimulants and other agents used in ADHD:
- No significant changes to QTc interval with long-term treatment with methylphenidate or amphetamine drugs.
- Atomoxetine can be associated with life-threatening long QT syndrome.
- Modafinil – no significant risk of QTc prolongation
- Clonidine and guanfacine – no significant increases
- AchE inhibitors have shown QTc prolongation in case reports. However, these case reports are in individuals 80 years or older with multiple medical comorbidities.
- No significant increase.
The risk of QTc prolongation increases when two medications with QTc prolongation risk are prescribed.
Several other non-psychotropic medications can prolong the QT interval.
As patients with psychiatric disorders can have other medical comorbidities, clinicians should be aware of the risks of combined treatment.
MANAGEMENT OF PROLONGED QTc INTERVAL
- The risk of QTc prolongation is to be weighed up against the risk of stopping medication which can result in a relapse or decompensation of psychiatric illness.
2. ECG monitoring
- In hospital settings, QTc monitoring is recommended before initiation or dose adjustment of QTc-prolonging agents, with follow-up ECG 8 to 12 h thereafter.
- According to the American Psychiatric Association Guidelines, clinicians should obtain a thorough medical and medication history and baseline ECG (within 1 month) prior to initiation of antipsychotics. However, the absence of a baseline ECG should not prevent antipsychotic prescribing. [Funk M et al., 2020]
3. Monitor for electrolyte disturbances
- Hypokalaemia, Hypocalcaemia and Hypomagnesemia can increase the risk of QT prolongation.
4. Prescribing principles:
- Avoid high-risk medications when baseline QTc interval is not immediately possible and consider lower-risk agents (QTc interval <10 msec)
- Baseline and follow-up ECG should be obtained whenever feasible for patients with two or more risk factors or any prior ECG demonstrating a QTc > 450 msec in male or > 470 msec in female patients
- An ECG within the previous 3–6 months in patients without new risk factors for QTc interval prolongation can be used for the baseline study if there are no new medical conditions.
5. Management: Reduce, Switch or Stop for following criteria
- Marked QTc interval prolongation (> 500 msec) OR
- Sudden increase of QTc interval (> 60 msec from baseline)
Psychotropics are associated with QTc interval prolongation, with some medications prolonging the QTc interval more than others.
A prolonged QTc interval, especially >500 msec increases the risk of Torsades de Pointes. (TdP)
Clinicians should be aware of the varied risk profiles of psychotropics concerning the QTc interval and take into account the various static and dynamic risk factors that prolong QT intervals.
A risk-benefit analysis should be carried out when prescribing medications that prolong QTc.