03. Torsades de Pointes: Impact of Antidepressants and Antipsychotics

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Torsades de Pointes: Rare but Lethal Arrhythmia

We’ve discussed psychiatric medications and their risk for QT prolongation or torsades de pointes before. Torsades is a lethal polymorphic ventricular arrhythmia associated with sudden cardiac death. Some patients get no warning symptoms —no palpitations, no dizziness—they just drop dead.

Torsades is highly recurrent, even in the short term. It may resolve on its own or respond to magnesium, but it frequently recurs within minutes to hours, sometimes repeatedly. Unfortunately, there’s no reliable way to predict who will develop torsades.

Currently, QT prolongation is considered the best approximation of torsades risk, though the relationship is inexact. Some medications, like amiodarone, cause significant QT prolongation but are rarely associated with torsades.

Psychiatric Medications and QT Prolongation

Many psychiatric medications have been linked to both QT prolongation and torsades risk. Interestingly, QT prolongation risk is reportedly the most common reason for FDA rejection of new medications. This is surprising, considering torsades is a rare event, occurring in only 1 in 12,000 to 1 in 120,000 cases.

Antidepressants, Antipsychotics, and Torsades

A recent case-control study published in General Hospital Psychiatry examined whether antidepressant and antipsychotic medications increase torsades risk. The authors looked at 110 torsades cases and matched them in a 3:1 ratio with 330 controls. Controls were just the three most recent EKGs before the torsades cases—no special matching criteria. They then looked at eight variables to identify associations with torsades.

Here’s the key takeaway:

• Monotherapy with antidepressants or antipsychotics was not associated with torsades
• Age, hepatic failure, and renal failure were not associated with increased risk
• Use of two or more antidepressants was associated with torsades
• Other risk factors included:
  • Use of other QT prolonging agents
  • Female sex
  • Left ventricular dysfunction
  • Acute MI
  • Hypokalemia (<3.5)

Of all these, the use of two antidepressants actually had the lowest relative risk, but it was still statistically significant. There was also a non-significant trend for torsades with the use of two or more antipsychotics. Medications were included if given within five days of the torsades event.

Unpacking the Study Results

The lack of association between monotherapy antidepressants or antipsychotics and torsades aligns with existing literature. Even medications with the highest QT prolongation potential (e.g., citalopram, ziprasidone, iloperidone, thioridazine) aren’t commonly linked to torsades or sudden cardiac death. This is partly due to torsades’ rarity and the relatively modest QT prolongation (10-20 ms) caused by these medications.

However, the study found that using two or more antidepressants was a significant torsades risk factor, while using two or more antipsychotics approached significance. This polypharmacy risk has been previously suggested, particularly for antipsychotics, where cumulative dose rather than multiple medications was thought to increase risk. But for antidepressants, this idea is newer. The authors speculate that needing two antidepressants might signal more severe illness, which itself could be linked to poor cardiac outcomes.

Antidepressant Augmentation and Torsades

Interestingly, antidepressants commonly used for augmentation (bupropion, mirtazapine, trazodone) were most frequently prescribed in torsades cases. While the study doesn’t speculate on this connection, it raises questions about these medications’ potential role in torsades risk.

• Bupropion: Generally cleared of QT prolongation risk. When a signal does appear, it seems to be an artifact—likely due to tachycardia and Bazett correction.
• Mirtazapine: Mixed evidence, one study did link it to higher sudden cardiac death, but causality wasn’t clear. Some cardiologists even think it’s safer than SSRIs, but there’s no strong data to back that up.
• Trazodone: It’s not widely known for QT effects, but a 2020 study found it prolonged QT more than ziprasidone in some cases.

Study Limitations and Future Directions

This study’s small sample size limits its ability to detect signals for individual agents. The findings regarding the so-called “other antidepressants” could be random or due to a failure to correct for multiple comparisons. However, these results are intriguing and warrant further investigation.

The study found a correlation between QT interval and torsades (501 ms in cases vs. 448 ms in controls). However, it’s important to avoid assigning arbitrary QT cutoffs for risk, as torsades can occur at lower QT values, and many patients with QTc >500 ms never experience torsades.

The study didn’t look at bradycardia, which is unfortunate. Many consider it the most important risk factor for torsades. That could be relevant here—lots of psychiatric meds slightly raise heart rate.

Reassuringly, only 2 of the 110 torsades patients died. That’s a low mortality rate, likely due to being in a monitored setting. Still, the torsades group had 3 times the overall mortality rate compared to controls.

Protecting High-Risk Patients

We need more studies on antidepressant and antipsychotic polypharmacy and their relation to torsades. But this study raises important questions.

For patients with multiple torsades risk factors who require psychiatric medications, an interesting development from psychedelic research might offer a solution. Ibogaine, a psychedelic used for addiction treatment, has significant QT prolonging properties and a history of sudden deaths.

More recently though, protocol has been developed for ibogaine that involves giving patients high doses of magnesium prior to treatment. This seems to reduce the torsades risk significantly. More studies are needed, but the early results are promising.

In the future, a similar approach could potentially be used for high-risk patients requiring antipsychotic medication, complementing thorough risk assessment and close cardiac monitoring.

Abstract

Impact of antidepressant and antipsychotic use in the occurence of torsades de pointes arrhythmia: a case-control study

Samuel Cyr, M.D. Lydia Abdelaziz, M.D., Anthony Minichiello, M.D., Maxime Bouvier, M.D., Orielle Djona, M.D., Céline Fiset, M.D., Rafik Tadros, M.D., Sylvie Levesque, M.D., Charline Daval, M.D., Viviane Lavigne, M.D., Paul Khairy, M.D., Stanley Nattel, M.D. & Judith Brouillette, M.D.

Objectives and methods

Psychotropic drugs may prolong the corrected QT interval (QTc), which has been associated with torsades de pointes (TdP). Our aim is to measure the relative impact of psychotropic drug use on TdP. A case-control study was conducted on 110 cases of confirmed TdP, and 330 matched controls. Hierarchical regression was performed by first including pre-identified risk factors (including demographic, medical conditions, and drugs such as antiarrhythmics) and then psychotropic drugs (antidepressants and antipsychotics). Population attributable risks (PAR) were calculated.

Results

At the time of admission, TdP was the primary, secondary, or complication diagnosis in 32.7 %, 30.9 %, and 36.4 % of cases, respectively. There were more patients with TdP who died during hospitalization compared to controls (7.3 % vs. 2.7 %, p < 0.05), but TdP was the cause of death in only two (1.8 %) of them. In our final regression model, age, hepatic and/or renal failure and antidepressant/antipsychotic drug monotherapy were not associated with TdP. On the other hand, the use of other QTc-prolonging drugs, female sex, left ventricular dysfunction, acute myocardial infarction, hypokalemia, and use of ≥ 2 antidepressants were all significantly associated with TdP, with PAR of 55.3 %, 41.8 %, 26.2 %, 13.0 %, 11.7 %, and 6.3 % respectively.

Conclusions

In analyses adjusting for concomitant conditions/drugs, antidepressant or antipsychotic monotherapy was not associated with TdP while the use of ≥ 2 antidepressants was. However in terms of PAR, the use of other QTc-prolonging drug, including antiarrhythmics, sex, and left ventricular dysfunction carried a higher burden than the use of ≥2 antidepressants. These findings may inform and assist in balancing the risks and benefits of psychotropic drugs.

Reference

Cyr, S. M.D., Abdelaziz, L. M.D., Minichiello, A. M.D., Bouvier, M. M.D., Djona, O. M.D., Fiset, C. M.D., Tadros, R. M.D., Levesque, S. M.D., Daval, C. M.D., Lavigne, V. M.D., Khairy, P. M.D., Nattel, S. M.D. & Brouillette, J. M.D. (2025). 

Impact of antidepressant and antipsychotic use in the occurence of torsades de pointes arrhythmia: a case-control study

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General Hospital Psychiatry
Volume 94

, May–June 2025, Pages 16-23.