Major depression with psychotic features (psychotic depression) is a prevalent diagnosis in the general population. Previous epidemiological studies have estimated that approximately 15% to 20% of patients with major depression have psychotic features, with the prevalence increasing to almost 45% in elderly patients with major depression.1 Fortunately, this is a condition that can be treated. A double-blind, randomized, controlled trial found that the most effective pharmacological treatment for the treatment of psychotic depression is a combination of olanzapine and sertraline.2 However, olanzapine, along with other second-generation (ie, atypical) antipsychotics, is known to have a tendency to prolong the QTc interval, putting the patient at risk for arrhythmias that can range from mild to as severe as Torsades de pointes and even death.
This article presents the case of an 80-year-old man who presented with a first-time episode of psychotic depression and was started on a combination of olanzapine and sertraline, complicated by a prolonged QTc. We felt the benefits of treating his psychotic symptoms outweighed the risk of possible arrhythmias, so we continued to provide medications to alleviate his delusions and hallucinations; however, we had to change his medication regimen to ensure that his QTc prolongation would not progress to a fatal arrhythmia. This article also presents safer options of treating major depression with psychotic features in regard to a patient's cardiac health.
The patient was an 80-year-old man who was admitted to our geriatric unit for symptoms of depression, suicidal ideation, paranoia, persecutory delusions, and auditory hallucinations. Laboratory results upon admission did not reveal a medical explanation for his symptoms; there was no leukocytosis, and troponins, urine toxicology screen, and urinalysis were all negative. Additionally, the patient's glucose, thyroid-stimulating hormone, folate, and vitamin B12 levels were within normal limits, his rapid plasma reagin was nonreactive, and a chest radiograph was without focal consolidation. Magnetic resonance imaging of the brain showed old infarcts but no acute findings suggestive of inflammatory, neoplastic, or infectious processes. Electroencephalogram did not show epileptiform or seizures. The patient's medical history was significant for sick sinus syndrome that was diagnosed and treated with permanent pacemaker placement. Family history was notable for unipolar depression in the patient's mother, daughter, and nephew.
On initial assessment, the patient admitted to having thoughts that people were trying to kill him, and hearing voices in his head “that do not say anything in particular.” He also reported suicidal ideations. He believed that the US government wanted to deport him, and he expressed a desire to have a press conference with the President regarding deportation. He also expressed delusions that there was a recording/monitoring device on his eyeglasses allowing the government to watch him. Collateral information from the patient's wife revealed that for the past few months the patient had a lack of desire to participate in his regular activities, decreased concentration, insomnia, a decreased appetite, low energy, and an overall depressed mood. In the emergency department, the patient was started on a regimen of olanzapine and sertraline for his psychiatric symptoms. However, after getting an electrocardiogram (ECG) in the geriatric unit, it was noted that the patient had a QTc interval of 524 ms, which was an increase from the interval of 501 ms measured in the emergency department. Because both of these intervals were above the upper limit of normal for men, we had to switch the patient from olanzapine to a medication that had a lower risk for QTc prolongation.
Although treatment with antipsychotics in patients with a prolonged QT is tricky at all ages, it becomes even more so in elderly patients. A systematic review of two large studies that investigated the effects of age on QT interval in nearly 56,000 people found that there is an increase in QT interval with an increase in age, with a steeper slope seen in people older than age 70 years.3 Furthermore, studies have shown that age-matched patients with cardiovascular disease tend to have longer QTc intervals than their counterparts who do not have cardiovascular disease.4 Therefore, our patient, an elderly male with prior cardiovascular disease, already had several factors that predisposed him to having a prolonged QTc. Consequently, it was extremely important for us to monitor this patient's ECG results and choose his pharmacotherapeutic treatment carefully.
There have been several studies published in the literature that aim to describe the effects of various antipsychotic agents on the QTc interval of patients taking these medications, with the goal of determining which of the drugs, if any, are relatively safer to use. One systematic review by Wenzel-Seifert et al.5 sought to report QTc prolongation caused by both typical and atypical antipsychotics. The investigators determined that of the typical antipsychotics, thioridazine is the one that prolongs the QTc to the highest extent (+28 ms to +36.6 ms), followed by pimozide (+19 ms + 24 ms) and haloperidol (+3.8 to +8.9 ms). Furthermore, the study describes that these three typical antipsychotics are also associated with an increased incidence of Torsades de pointes, especially when haloperidol was administered intravenously. Among the atypical antipsychotics, the investigators report that sertindole (+11 ms to +30 ms) and ziprasidone (+9.7 ms) prolong the QTc to the greatest extent. The atypical antipsychotic most associated with inducing Torsades de pointes was ziprasidone, with 28 reported cases in a 3-year period (2004–2007). In this study, olanzapine was found to cause mild to moderate QTc prolongation (−4.5 ms to +8.4 ms).5 Although olanzapine was not the most dangerous atypical antipsychotic in regard to the conduction effects it had on the heart, this patient's heart was significantly affected by the medication, and we were cognizant of the fact that we had to treat his psychosis with a different antipsychotic.
Aripiprazole, a partial agonist at the dopamine-2 receptor, has been shown to be associated with the lowest risk of QTc prolongation in several studies. The systematic review by Wenzel-Seifert et al.5 mentioned above was unable to identify a single case in which aripiprazole prolonged the QTc interval; on the contrary, that literature review revealed that this medication is capable of reducing the interval (−4 ms to −3.5 ms). A cross-sectional study conducted in Italy found that people who were taking aripiprazole had a significantly reduced likelihood of experiencing QTc prolongation; these results held true even after controlling for polypharmacy and for dosage of the antipsychotic.6 A Japanese study of patients with schizophrenia observed the effects on QTc of changing treatment from olanzapine to aripiprazole and found that the mean QTc decreased from 403.8 ms to 390.7 ms when this change in medication was made.7 However, because aripiprazole is not the first-line antipsychotic used to treat psychotic depression, it was important to consider that it may not be as effective as olanzapine in treating our patient's psychotic symptoms.
After reading several studies, the team made the decision to change the patient's medication from olanzapine to aripiprazole, despite knowing that his psychotic symptoms may not be as well controlled as they had been with olanzapine. Within 3 days of switching the medication, we saw a significant decrease in the QTc interval from 524 to 501 ms, and then down to 484 ms after 7 days. Additionally, the patient's psychotic symptoms continued to improve, with a decreased frequency of his auditory hallucinations and a decreased intensity of his persecutory delusions. Therefore, in our patient, treatment with aripiprazole was significantly safer to his heart and still effective enough to treat the psychotic features of his depression. Although the treatment of major depressive disorder with psychotic features may have recommended treatments, it is important to always balance the risk and benefits of each pharmacotherapeutic treatment and individualize the management of the patient being treated.
- Meyers BS, Flint AJ, Rothschild AJ, et al. STOP-PD Group. A double-blind randomized controlled trial of olanzapine plus sertraline vs olanzapine plus placebo for psychotic depression: the study of pharmacotherapy of psychotic depression (STOP-PD). Arch Gen Psychiatry. 2009;66(8):838–847. doi:10.1001/archgenpsychiatry.2009.79 [CrossRef] PMID:19652123
- Zolas PT, Sher A. Antipsychotic drugs: a review with a focus on QT prolongation. www.iiste.org/Journals/index.php/JPAM/article/view/9688. Accessed February 4, 2020.
- Rabkin SW. Aging effects on QT interval: implications for cardiac safety of antipsychotic drugs. J Geriatr Cardiol. 2014;11(1):20–25. doi:10.3969/j.issn.1671-5411.2014.01.005 [CrossRef]
- Vieweg WV. New generation antipsychotic drugs and QTc interval prolongation. Prim Care Companion J Clin Psychiatry. 2003;5(5):205–215. doi:10.4088/PCC.v05n0504 [CrossRef] PMID:15213787
- Wenzel-Seifert K, Wittmann M, Haen E. QTc prolongation by psychotropic drugs and the risk of Torsade de Pointes. Dtsch Arztebl Int. 2011;108(41):687–693. doi:10.3238/arztebl.2011.0687 [CrossRef] PMID:22114630
- Barbui C, Bighelli I, Carrà G, et al. STAR Network Investigators. Antipsychotic dose mediates the association between polypharmacy and corrected QT interval. PLoS One. 2016;11(2):e0148212. doi:10.1371/journal.pone.0148212 [CrossRef] PMID:26840602
- Suzuki Y, Sugai T, Ono S, et al. Changes in the metabolic parameters and QTc interval after switching from olanzapine to aripiprazole in Japanese patients with stable schizophrenia. J Clin Psychopharmacol. 2011;31(4):526–528. doi:10.1097/JCP.0b013e318221e80d [CrossRef] PMID:21720226