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2. Cardiac Effects of Antipsychotics: QTc Prolongation
Scott R. Beach, M.D.
Attending Psychiatrist, Massachusetts General Hospital
Assistant Professor of Psychiatry, Harvard Medical School

3. QT Prolongation in First-Generation Antipsychotics
Thioridazine
Chlorpromazine
Mesoridazine
First-generation antipsychotics are linked to greater QT prolongation than second-generation agents. 
Carrà, G., Crocamo, C., Bartoli, F., Lax, A., Tremolada, M., Lucii, C., ... & Castellazzi, M. (2016). First‐generation antipsychotics and QTc: any role for mediating variables?. Human Psychopharmacology: Clinical and Experimental, 31(4),

4. Haloperidol QT Prolongation
Controversial
Effect is similar to
several second-generation antipsychotics
A greater risk for:
Ventricular arrhythmias
Sudden cardiac death
Carrà, G., Crocamo, C., Bartoli, F., Lax, A., Tremolada, M., Lucii, C., ... & Castellazzi, M. (2016). First‐generation antipsychotics and QTc: any role for mediating variables?. Human Psychopharmacology: Clinical and Experimental, 31(4),

5. QT Prolongation and Torsade in Intravenous Haloperidol
cases
Involved QT prolongation 58
Involved torsade de pointes 54
Underlying cardiac conditions 32
On agents known to prolong the QT interval 39
Carrà, G., Crocamo, C., Bartoli, F., Lax, A., Tremolada, M., Lucii, C., ... & Castellazzi, M. (2016). First‐generation antipsychotics and QTc: any role for mediating variables?. Human Psychopharmacology: Clinical and Experimental, 31(4),

6. QT Prolongation and Ziprasidone
2002
In combination with other QT-prolonging agents
In patients with a history of cardiac arrhythmias
Black box warning P Q R S T
QT Interval
The average QT prolongation: 10 to 21 ms P Q R S T
QT Interval
Up to 20%:
prolongation greater than 60 ms

7. Comparing QT Prolongation of Second-Generation Antipsychotics
Ziprasidone
Iloperidone
Leucht, S., Cipriani, A., Spineli, L., Mavridis, D., Örey, D., Richter, F., ... & Kissling, W. (2013). Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. The Lancet, 382(9896),

8. Quetiapine
2011
Avoid with other QT-prolonging agents in patients with: 
History of arrhythmia.
Metabolic deficits at increased risk for QT prolongation.
Up to 20% of patients experience a prolongation of greater than 20 ms. 
Leucht, S., Cipriani, A., Spineli, L., Mavridis, D., Örey, D., Richter, F., ... & Kissling, W. (2013). Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. The Lancet, 382(9896),
Leonard, C. E., Freeman, C. P., Newcomb, C. W., Bilker, W. B., Kimmel, S. E., Strom, B. L., & Hennessy, S. (2013). Antipsychotics and the risks of sudden cardiac death and all-cause death: cohort studies in Medicaid and dually-eligible Medicaid-Medicare beneficiaries of five states. Journal of clinical & experimental cardiology, (6), 1.

9. Second-Generation Antipsychotics with the Least QT prolongation
Aripiprazole
Lurasidone
Olanzapine
Risperidone
Clozapine
Leonard, C. E., Freeman, C. P., Newcomb, C. W., Bilker, W. B., Kimmel, S. E., Strom, B. L., & Hennessy, S. (2013). Antipsychotics and the risks of sudden cardiac death and all-cause death: cohort studies in Medicaid and dually-eligible Medicaid-Medicare beneficiaries of five states. Journal of clinical & experimental cardiology, (6), 1.
Ozeki, Y., Fujii, K., Kurimoto, N., Yamada, N., Okawa, M., Aoki, T., ... & Kunugi, H. (2010). QTc prolongation and antipsychotic medications in a sample of 1017 patients with schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 34(2),

10. Does Antipsychotic Polypharmacy Lead to Greater QT Prolongation?
If yes, it is mediated by:
The total cumulative dose. 
The total cumulative relative dose. 
Leonard, C. E., Freeman, C. P., Newcomb, C. W., Bilker, W. B., Kimmel, S. E., Strom, B. L., & Hennessy, S. (2013). Antipsychotics and the risks of sudden cardiac death and all-cause death: cohort studies in Medicaid and dually-eligible Medicaid-Medicare beneficiaries of five states. Journal of clinical & experimental cardiology, (6), 1.
Ozeki, Y., Fujii, K., Kurimoto, N., Yamada, N., Okawa, M., Aoki, T., ... & Kunugi, H. (2010). QTc prolongation and antipsychotic medications in a sample of 1017 patients with schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 34(2),

11. Antipsychotics and Their Impact on QT Prolongation
RISK
Aripiprazole
Lurasidone
Ziprasidone
Iloperidone
Thioridazine
? Intravenous haloperidol
Leonard, C. E., Freeman, C. P., Newcomb, C. W., Bilker, W. B., Kimmel, S. E., Strom, B. L., & Hennessy, S. (2013). Antipsychotics and the risks of sudden cardiac death and all-cause death: cohort studies in Medicaid and dually-eligible Medicaid-Medicare beneficiaries of five states. Journal of clinical & experimental cardiology, (6), 1.
Ozeki, Y., Fujii, K., Kurimoto, N., Yamada, N., Okawa, M., Aoki, T., ... & Kunugi, H. (2010). QTc prolongation and antipsychotic medications in a sample of 1017 patients with schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 34(2),

12. How to Use Antipsychotics in Patients at Risk?
Baseline EKG
At least 1 follow-up EKG
Replete electrolytes:
2 mEq
Magnesium
4 mEq
Potassium
Monitor other medications that:
Prolong QT. 
Interact with haloperidol.
If QT greater than 500 ms:
Consider adjunctive agents for managing delirium
Howland, R. H. (2014). Atypical antipsychotics are not all alike: side effects and risk assessment. 
Journal of psychosocial nursing and mental health services, 52(9),

13. Antipsychotics in the Outpatient Setting
Recommended monitoring for:
Thioridazine
Ziprasidone
Iloperidone
For patients with multiple risk factors for QT prolongation, obtain:
EKG at baseline. 
EKG intermittently after initiation.
Howland, R. H. (2014). Atypical antipsychotics are not all alike: side effects and risk assessment. 
Journal of psychosocial nursing and mental health services, 52(9),

14. Key Points
Thioridazine, ziprasidone, and iloperidone are the antipsychotics associated with the most QT prolongation. 
Intravenous haloperidol has been associated with QT prolongation and torsade in various case reports, though it appears to be a very rare occurrence.
Intravenous haloperidol is often prescribed to the sickest patients in the hospital, which may confound the association.
Aripiprazole and lurasidone appear to have the least association with QT prolongation among the antipsychotics and are generally considered safe.

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