Cardiovascular Risks of Fluphenazine in a Patient With Schizophrenia

Abstract

Objective: Patients with psychiatric illnesses are at an increased risk for heart disease, and many antipsychotic medications elicit adverse effects on the heart. This report summarizes conduction abnormalities manifested as chest pain when a patient is treated with fluphenazine decanoate. Case Summary: A 61-year-old male with a history of schizophrenia, coronary artery disease, and atrial fibrillation presented complaining of chest pain and shortness of breath with moderate T-wave abnormality detected on electrocardiogram. The patient recently initiated fluphenazine decanoate intramuscular injection while continuing oral fluphenazine as directed. Discussion: Utilizing the Naranjo algorithm, the cardiac conduction abnormality was determined to be a possible adverse event associated with fluphenazine use. This was based on recent initiation and increasing dose of fluphenazine and documented association of antipsychotics and risk of Torsades de Pointes. Conclusions: While it is known that fluphenazine decanoate can cause extrapyramidal adverse effects, this case demonstrates that it may also play a role in causing or exacerbating cardiovascular adverse events. Continued cardiovascular monitoring after starting fluphenazine decanoate is warranted.

Introduction

Antipsychotics used to treat schizophrenia can be grouped into 2 main classes, first generation and second generation, based on their mechanism of action.^1,2 First-generation antipsychotics (FGAs) exert their primary antagonistic effect on dopamine D₂ receptors, while second-generation antipsychotics (SGAs) have a strong affinity for both serotonin 5HT_2A receptors and dopamine D₂ receptors. Fluphenazine is a member of the FGA class and is available as a decanoate, a long-acting formulation that is administered by intramuscular or subcutaneous injection. The long duration of action, approximately 2 to 4 weeks, is due to the hydrolysis of the prodrug by esterases, which slowly releases the active compound.² This extended duration is especially useful in patients who are nonadherent to daily administered medications.^2,3

Extrapyramidal symptoms are a well-known adverse effect of fluphenazine and other antipsychotics as stated in the prescribing information, previous case reports, drug databases, and pharmacologic textbooks. These adverse effects are associated with fluphenazine because it targets and has high affinity for dopamine D₂ receptors.^1,3-5 Extrapyramidal adverse effects include pseudoparkinsonism, dystonia or muscle spasm, akathisia, and tardive dyskinesia.^1,6 However, cardiovascular adverse effects attributed to fluphenazine, especially those resulting in electrocardiographic changes, are reported less frequently in the literature.

A literature search was conducted through PubMed and MEDLINE databases using the search terms fluphenazine adverse event, fluphenazine cardiac adverse event, and fluphenazine/adverse effects. Few published articles correlated fluphenazine with arrhythmia, as demonstrated in this case. There are data to show arrhythmias, specifically prolonged QT interval and Torsades de Pointes (TdP), may occur with antipsychotic use.⁷ In recent years, the Food and Drug Administration (FDA) has updated antipsychotic safety warnings with regard to cardiovascular risk. SGAs obtained a black box warning on the increased risk of death, most likely due to cardiovascular or infectious causes, in elderly patients with dementia-related psychosis in 2005 and this same warning was applied to FGAs in 2008.⁸ A risk of TdP/QT prolongation was added to the labeling of haloperidol in 2007.⁹ The patient case detailed below demonstrates not only the common extrapyramidal symptoms associated with FGA initiation, but also reveals the possible role of fluphenazine in exacerbating cardiac symptoms in a high-risk patient with schizophrenia.

Case Presentation

A 61-year-old white male presented to the emergency department (ED) complaining of shortness of breath along with constant diffuse chest pain that started 30 minutes prior to arrival. On arrival to the ED, the patient was somnolent but able to be aroused with diffuse tremors, dyskinesia, and was still complaining of shortness of breath.

After contacting the patient’s primary pharmacy, it was determined that the patient recently started taking fluphenazine. Prescriptions for fluphenazine decanoate 25 mg intramuscularly (IM) followed by 50 mg IM in 2 weeks, as well as fluphenazine 5 mg 1 to 2 tablets by mouth daily as directed were on file. The first fluphenazine injection was administered approximately 2 weeks prior to presentation, and the second IM injection was due on the day the patient presented to the ED. Relevant oral medications the patient was taking at home included carvedilol 3.125 mg twice daily, clonazepam 0.5 mg twice daily and 1 mg at bedtime, apixaban 5 mg twice daily, atorvastatin 20 mg at bedtime, lisinopril 10 mg daily, nitroglycerin 0.4 mg sublingually as needed, clopidogrel 75 mg daily, ranolazine extended release 500 mg twice daily, and tramadol 50 mg every 4 hours as needed. The patient’s prior antipsychotic medications included haloperidol and ziprasidone according to the hospital-wide database. His past medical history is significant for bipolar disorder, paranoia, schizophrenia, atrial fibrillation, coronary artery disease, angina, congestive heart failure, myocardial infarction, hypertension, and 5 cardiac catheterizations between 2009 and 2016.

His vital signs on presentation were a temperature of 36.8°C, heart rate of 67 beats per minute, respiratory rate of 16 breaths per minute, blood pressure of 137/100 mm Hg, and 98% oxygen saturation on room air. Laboratory testing performed in the ED revealed the following: serum and urine drug screens were negative, blood urea nitrogen elevated at 24 mg/dL, serum creatinine of 1.25 mg/dL, and troponin-negative. Chest X-ray indicated mild presumed atelectasis in the left lateral lung base and normal pulmonary vascularity. The electrocardiogram (ECG) showed atrial fibrillation with aberrant conduction or ventricular premature complexes and moderate T-wave abnormality.

The patient was previously seen in the ED 3 days prior to this encounter for chest pain and was negative for troponin. Complete blood count and chest X-ray were normal, and the patient was discharged with a prescription for tramadol 50 mg every 4 hours as needed, as stated above in the medication history. Three days prior to that he was admitted to the hospital for chest pain, hematemesis, and dizziness with syncope. One month prior to that he had his most recent cardiac catheterization with percutaneous coronary intervention.

On reassessing the patient, approximately 60 minutes after presentation, the physician noted he was more conversational with lessened tremors and reported improvement in symptoms following administration of lorazepam and fluids. The physician’s diagnosis was acute exacerbation of chronic chest pain and acute diffuse tremors suspected as secondary to fluphenazine. The patient was instructed to start benztropine 1 mg twice daily for 30 days and to follow-up with his primary care physician in 2 days. The chest pain was determined to have an uncertain cause.

Discussion

A previously published case report associated fluphenazine decanoate with atrioventricular (AV) block.¹⁰ Fluphenazine decanoate was discontinued and the patient was treated with atropine. The patient was rechallenged and developed AV block 5 days later. The electrophysiological effects and electrocardiographic changes provoked by phenothiazines, fluphenazine being one of these, include widening, notching, flattening, or inversion of the T-wave and prolongation of the QT interval.

In our patient case, a complete medication history and physical evaluation was performed on entry to the ED. The case report was narrated based on hospital documentation in the electronic medical record and witnessed patient evaluation in the ED. The details relayed above are factual and accurate depictions of the patient ED visit. The Naranjo algorithm was utilized to determine the likelihood of the ECG changes to be related to fluphenazine.¹¹ It was determined to be a possible adverse event due to the recent initiation of the medication and increasing the IM dose while continuing the oral formulation, as well as the documented association of antipsychotics and risk of TdP.⁸ Fluphenazine is currently not classified in any of the 4 QT risk categories on the CredibleMeds list of drugs that prolong QT and may induce TdP.¹² The CredibleMeds QT drugs list is managed by the Arizona Center for Education and Research on Therapeutics, which is under contract with the FDA’s Safe Use Initiative. One study analyzed adverse event reports submitted to the FDA Adverse Event Reporting System and categorized the torsadogenic signal of antipsychotics.⁸ In this study, drugs were placed in different groups based on meeting the following criteria: at least 4 cases of TdP/QT abnormalities, significant reporting odds ratio (ROR) for TdP/QT abnormalities, at least 4 cases of ventricular arrhythmia/sudden cardiac death, significant ROR for ventricular arrhythmia/sudden cardiac death, and significant unadjusted and unstratified ROR that persists throughout a cumulative approach. If a drug met all 5 criteria then it was classified as group A, while group B drugs had to meet only 4 of the criteria. The study placed fluphenazine in the B rating group indicating a strong signal. Group A drugs, those with very strong torsadogenic signal, consisted primarily of SGAs. Of the 7 categorized group B drugs, 6 were FGAs. Olanzapine, quetiapine, and clozapine were the most often reported and obtained the greatest amount of reports for events of interest, including TdP and sudden cardiac death. Also, it is important to note that according to the fluphenazine prescribing information, listed cardiac adverse reactions are hypertension, fluctuations in blood pressure, and hypotension (rarely).¹³ Other relevant adverse events reported include altered electrocardiographic tracings and hypotension that is severe enough to cause fatal cardiac arrest.

The significant details to address in our patient case include the fact that the patient was administered the long-acting IM formulation as well as the oral formulation of fluphenazine, which could increase the risk of cardiac abnormalities in this specific patient; however, there is not enough published evidence to clearly state that this adverse effect is dose-dependent. A cardiac conduction change, moderate T-wave abnormality, was detected in the ED, and the patient presented with physical chest pain as an emergent symptom 12 days after receiving the fluphenazine injection. It should also be noted that this patient has several cardiovascular comorbidities with his history of multiple cardiac catheterizations, hypertension, atrial fibrillation, mental illness, and older age.

Limitations and confounding factors are present in our patient case. The patient had several underlying cardiovascular conditions including hypertension, atrial fibrillation, congestive heart failure, and previous myocardial infarction, which can contribute to ECG changes. Although discontinued more than 8 months prior to admission, the patient’s previous use of haloperidol and ziprasidone and concern for polypharmacy could have a cumulative cardiovascular effect causing the adverse event. However, these agents alone are unlikely to have contributed to the patient’s clinical presentation, as the patient had been using them longer than 8 months. Also, the patient was prescribed the fluphenazine decanoate IM injection as well as fluphenazine orally as directed, but it was not determined how often the patient was taking the oral formulation. This patient may have also been at increased cardiovascular risk due to his schizophrenia because cardiac disorders such as coronary artery disease and chronic ischemic heart disease are more common in those with psychiatric conditions.^14,15

This case provides emphasis for continuing to assess the risk and benefit analysis in each patient prescribed an antipsychotic, whether it be a FGA or a SGA. This is especially true for antipsychotics that have an increased risk of cardiac conduction abnormalities. Clinical management algorithms have been developed recently that can help clinicians in determining patient risk. One developed by Fanoe et al states that when deciding to initiate drugs associated with even possible QT prolongation or arrhythmias, a patient’s cardiac risk profile should be assessed.¹⁴ This assessment includes family history, known cardiac disease, other QT-prolonging drugs used concomitantly, cardiac symptoms like palpitations or angina, ECG, and age. If positive findings are present, consider assessment by a cardiologist and reconsider choice of drug, particularly to an agent without QT prolongation risk. However, an alternative agent is not always an option. In that case, a prescriber must decide whether it is either more beneficial to control the symptoms of schizophrenia (and possibly increasing the cardiovascular risk) or to allow the patient to go untreated, which also poses an inherent risk. Regardless of the decision that is made, the lowest effective dose should be prescribed. Regular ECG monitoring and evaluation of new cardiac symptoms should be conducted 1 to 2 weeks after initiation and after increases in dose.

Conclusion

According to the summarized patient case and literature search results, fluphenazine may play a role in causing or exacerbating cardiovascular conduction abnormalities. Caution should be used when prescribing fluphenazine and other antipsychotics, especially in patients who are at a higher risk for cardiovascular comorbidities based on family history, significant past medical history, advanced age, and so on. The risks and benefits must be weighed individually for each patient and appropriate routine monitoring should be performed. QT prolonging drug lists, prescribing information, and postmarketing reports should be utilized to gauge cardiovascular risk of specific antipsychotics. Suspected antipsychotic-induced cardiovascular effects should continue to be reported to gather stronger evidence for the possible relationship between antipsychotics and cardiovascular effects.

Key Points

1. Patients with schizophrenia are at increased risk for heart disease and many antipsychotic agents, the mainstay of schizophrenic treatment, elicit cardiovascular adverse events.

2. Fluphenazine decanoate may play a role in causing or exacerbating cardiovascular adverse events like conduction abnormalities.

3. Patient-specific factors, such as past medical history, concomitant medications, and age, should be collected and used to select an appropriate antipsychotic therapy and necessary monitoring should be performed after initiation.