QTc Prolongation and Psychotropics- Management of Prolonged QTc interval in Psychiatry

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.

1.Bazzet’s Formula:

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.

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.

Static factors: 

• 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

Dynamic Factors:

1. Two or more QTc-prolonging agents
2. Pharmacological plan for drug-interactions and drug toxicity
3. Rapid intravenous infusion of QTc interval prolonging drugs
4. Severe acute systemic illness
5. Bradycardia
6. Starvation
7. Inadequate dose adjustment of hepatically metabolised drugs in patients with hepatic sclerosis
8. Inadequate dose adjustment of renally eliminated drugs in patients with acute kidney or intercurrent kidney disease
9. Risk or presence of hypokalaemia, hypomagnesaemia or hypocalcaemia

As many as 75% of TdP cases occur at therapeutic doses of antipsychotic medications.

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).

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]

• Methadone shows a dose-dependent QTc prolongation (oral methadone) with an approximately 10 msec increase in QTc for every 50 mg daily dose increase.

Mood stabilisers: 

• 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

• 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]