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QTc-Interval Abnormalities and Psychotropic Drug Therapy in Psychiatric Patients 

QTc-Interval Abnormalities and Psychotropic Drug Therapy in Psychiatric Patients
Chapter:
QTc-Interval Abnormalities and Psychotropic Drug Therapy in Psychiatric Patients
Author(s):

Amanda Sun

, and Vinod H. Srihari

DOI:
10.1093/med/9780190625085.003.0037
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The confirmation of a link between QT-interval abnormalities and high-dose prescribing supports current guidelines for electrocardiographic screening, but our results suggest that monitoring is also needed in patients taking tricyclic antidepressants, droperidol, and thioridazine, particularly if other risk factors are present.

Reilly et al.1

Research Question:

Is QTc prolongation associated with specific psychotropic medications, the dose, or other factors?

Funding:

Northern Regional National Health Service and Medical Research Council

Year Study Began:

1994

Year Study Published:

2000

Study Location:

Mental health facilities (inpatient, day hospital, outpatient) in six districts in northeast England

Who Was Studied:

18 to 74-year-old psychiatric patients, some of whom were on psychotropic medications, and healthy volunteers. Notably, subjects with pre-existing cardiac disease were included in the psychiatric patients group.

Who Was Excluded:

Among the psychiatric patients, patients who failed to provide informed written consent, underwent a change in drug therapy within the last two weeks (or last three months for patients on depot medications), or had a history of atrial fibrillation or bundle branch block were excluded. Those with “overt cardiovascular disease” were excluded from the healthy reference group to minimize the impact of pre-existing cardiac disease on the measurement of normal QTc.

How Many Participants:

495 psychiatric patients, 101 healthy volunteers

Study Overview:

See Figure 37.1 for a summary of the study design.

Figure 37.1 Summary of Study Design

Figure 37.1 Summary of Study Design

note: EKG = electrocardiography.

Study Implementation:

The researchers performed 12-lead electrocardiograms (EKG) on the healthy volunteer group and psychiatric patients. The QTc values obtained from the healthy reference group were used to define abnormal QTc as greater than 456 ms, two standard deviations above the mean value in the group. The researchers then conducted logistic regression analyses to examine various predictive variables for QTc prolongation in the psychiatric patient group. They also examined the impact of QTc dispersion (defined as the difference between the minimum and maximum QTc on the 12-lead EKG) and T-wave abnormality (defined as the presence of inversion, flattening, or bifid T wave) as secondary outcomes, both of which are associated with increased cardiac events.

The investigators looked at the impact of demographic variables, psychiatric disorders and drug therapy such as antipsychotics, selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, benzodiazepines, and mood stabilizers on the presence of EKG changes. Pharmacotherapy use was defined as use for more than one week (for oral medications) and more than two months (for long-acting injectable medications). Antipsychotic dose category was determined by conversion into chlorpromazine equivalents (standard: 0–1,000 mg chlorpromazine equivalents per day; high: 1,001–2,000 mg chlorpromazine equivalents per day; very high: >2,000 mg chlorpromazine equivalents per day).

Follow-Up:

This study was a cross-sectional study, and patients were not followed longitudinally.

Endpoints:

Rate-corrected QT interval (QTc), unadjusted QTc dispersion, and T wave abnormalities (inversion, flattening, or bifid) on electrocardiogram

Results

  • Age over 65 years, use of tricyclic antidepressants, and use of droperidol or thioridazine were found to be significantly associated with QTc prolongation, based on logistic regression analyses and confirmed by backwards stepwise regression.

  • Increased antipsychotic dose was associated with increased risk for QTc lengthening.

  • QT dispersion and T-wave abnormalities were not significantly associated with antipsychotic treatment but were associated with lithium use (Tables 37.1 and 37.2).

Table 37.1 Summary of Study Key Findings: Significant Risk Factors for QTc Lengthening by Logistic Regression and Backwards Stepwise Regression

Risk factor

Adjusted odds ratio from full model

P value

Demographics

Age >65

3.0

0.04

Drug Therapy

Droperidol

6.7

0.004

Thioridazine

5.3

<0.001

Tricyclics

4.4

0.004

Table 37.2 Summary of Study Key Findings: Antipsychotic Dose and Risk of QTc Prolongation

Risk factor

Adjusted odds ratio from full model

P value

Antipsychotic

Low dose

1.4

0.52

High dose

5.4

0.03

Very high dose

8.2

0.01

Criticisms and Limitations:

The cross-sectional design with use of logistic regression can provide only weak evidence of causality, and these results should thus these findings should be interpreted with caution. The study excluded severely ill inpatients and those with atrial fibrillation and bundle branch block, which decreases generalizability. Additionally, the study evaluated over 30 different psychotropic drugs, and many patients were on more than one drug, which limited the study’s ability to evaluate effects of individual drugs. Finally, the study used QTc as a surrogate risk factor for clinically significant cardiac events but did not report on frequency of arrhythmias or sudden death.

Other Relevant Studies and Information:

  • For further information on QTc prolongation with antipsychotics (including more second-generation antipsychotics) and additional data on their comparative efficacy and tolerability, see the meta-analysis2 on this topic.

  • There have been other trials that studied the effects of psychotropic medications on QTc.3,4

  • According to the Berkshire Healthcare National Health Service antipsychotic prescribing guidelines,5 a baseline EKG should be obtained on initiation of an antipsychotic, and QTc should be followed at least annually. In the early stages of high-dose treatment and in patients with a cardiac history, the EKG should be repeated every few days during dose escalation and then every one to three months. Care should be taken especially with thioridazine, pimozide, droperidol, and haloperidol and the second-generation antipsychotic ziprasidone,6 whereas lurasidone, clozapine, and arpiprazole may have lower risks of QTc prolongation.7

  • According to the American Psychiatric Association, providers should reduce or discontinue the offending agent if the EKG shows an absolute QTc interval of >500 msec or an increase of 60 msec from baseline.8 Given the dose-dependent nature of QTc prolongation, prescribers should use the lowest dose of antipsychotic possible.

Summary and Implications:

In patients on psychotropic medications, in particular tricyclic antidepressants, high-dose antipsychotics and droperidol or thioridazine, QTc interval should be closely monitored by routine electrocardiography. Caution should also be exercised among patients on these agents in combination with lithium. Findings from this and other studies have contributed to shifts in prescribing practices for antipsychotic agents, including a reduction in the use of droperidol and thioridazine and lower dosing of antipsychotics.

Clinical Case: Choice of Psychotropic Drug in Patients with Psychiatric Illness and QTc Prolongation

Case History

A 67-year-old veteran with a history of coronary artery disease, hypertension, and schizoaffective disorder, depressive type, presents to the Veterans Affairs psychiatric emergency department and is admitted for worsening psychosis (despite good adherence to high-dose droperidol), severe depressed mood, and suicidal ideation. He endorses poor sleep and appetite, low self-worth, depressed mood, and thoughts of suicide by hanging. He demonstrates profound thought disorganization and paranoia about staff at his rest home wanting to hurt him. On routine admission EKG, patient is found to have an increased QTc of 514. According to the patient, and confirmed in the record, he benefited significantly during past and separate trials of nortriptyline and sertraline (that had been added to his antipsychotic treatment) to target depressive symptoms.

Based on the results of this study, what psychopharmacological approaches are safest?

Suggested Answer

This study raises concerns that tricyclic antidepressants and droperidol could each have contributed to QTc lengthening in this patient. He is typical of patients included in this study and, given his older age, is also more susceptible to QTc prolongation. If selecting an antidepressant, the team should counsel the patient to prefer sertraline over nortriptyline. They should also consider switching the patient’s antipsychotic (since dose reduction would threaten symptom control) and consider clozapine as one option that could multiply target worsening psychosis and suicidality, with a likely lower risk of QTc prolongation.

References

1. Reilly, J. G., Ayis, S. A., Ferrier, I. N., Jones, S. J., & Thomas, S. H. (2000). QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet, 355(9209), 1048–1052.Find this resource:

2. Leucht, S., Cipriani, A., Spineli, L., Mavridis, D., Orey, D., Richter, F., . . . Davis, J. M. (2013). Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: A multiple-treatments meta-analysis. Lancet, 382(9896), 951–962.Find this resource:

    3. Wenzel-Seifert, K., Wittmann, M., & Haen, E. (2011). QTc prolongation by psychotropic drugs and the risk of Torsade de Pointes. Deutsches Ärzteblatt International, 108(41), 687–693.Find this resource:

      4. van Noord, C., Straus, S. M., Sturkenboom, M. C., Hofman, A., Aarnoudse, A. J. L., Bagnardi, V., . . . Stricker, B. H. (2009). Psychotropic drugs associated with corrected QT interval prolongation. Journal of Clinical Psychopharmacology, 29(1), 9–15.Find this resource:

      5. Sims, K., Hewitt, K., Raynes, A., Tahir, O., and Booth, D. (2011). Antipsychotic guidelines: Treatment of schizophrenia and psychosis. Bracknell, UK: Berkshire Healthcare NHS Foundation Trust.Find this resource:

        6. Glassman, A. H., & Bigger, J. T. (2001). Antipsychotic drugs: Prolonged QTc interval, torsade de pointes, and sudden death. American Journal of Psychiatry, 158(11), 1774–1782.Find this resource:

        7. Ries, R., & Sayadipour, A. (2014). Management of psychosis and agitation in medical-surgical patients who have or are at risk for prolonged QT interval. Journal of Psychiatric Practice, 20(5), 338–344.Find this resource:

        8. Lieberman, J. A., Merrill, D., & Parameswaran, S. (2009). APA guidance on the use of antipsychotic drugs and cardiac sudden death. Washington, DC: APA Council on Research.Find this resource: