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QTc Interval Prolongation with Therapies Used to Treat Patients with Parkinson’s Disease Psychosis: A Narrative Review

Authors Torres-Yaghi Y, Carwin A, Carolan J, Nakano S, Amjad F, Pagan F

Received 10 June 2021

Accepted for publication 19 November 2021

Published 24 December 2021 Volume 2021:17 Pages 3791—3818

DOI https://doi.org/10.2147/NDT.S324145

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 4

Editor who approved publication: Dr Roger Pinder



Yasar Torres-Yaghi, Amelia Carwin, Jacob Carolan, Steven Nakano, Fahd Amjad, Fernando Pagan

Department of Neurology, National Parkinson’s Foundation Center for Excellence, Translational Neurotherapeutics Program, Movement Disorders Program, MedStar Georgetown University Hospital, Washington, DC, USA

Correspondence: Yasar Torres-Yaghi
MedStar Georgetown University Hospital, Department of Neurology, National Parkinson’s Foundation Center for Excellence, Translational Neurotherapeutics Program, Movement Disorders Program, 3800 Reservoir Road, NW, Washington, DC, 20007, USA
Tel +1 202-444-6087
Fax +1 202-444-2186
Email [email protected]

Abstract: In addition to the classic motor symptoms of Parkinson’s disease (PD), people with PD frequently experience nonmotor symptoms that can include autonomic dysfunction and neuropsychiatric symptoms such as PD psychosis (PDP). Common patient characteristics, including older age, use of multiple medications, and arrhythmias, are associated with increased risk of corrected QT interval (QTc) prolongation, and treatments for PDP (antipsychotics, dementia medications) may further increase this risk. This review evaluates how medications used to treat PDP affect QTc interval from literature indexed in the PubMed and Embase databases. Although not indicated for the treatment of psychosis, dementia therapies such as donepezil, rivastigmine, memantine, and galantamine are often used with or without antipsychotics and have minimal effects on QTc interval. Among the antipsychotics, data suggesting clinically meaningful QTc interval prolongation are limited. However, many antipsychotics have other safety concerns. Aripiprazole, olanzapine, and risperidone negatively affect motor function and are not recommended for PDP. Quetiapine is often sedating, can exacerbate underlying neurogenic orthostatic hypotension, and may prolong the QTc interval. Pimavanserin was approved by the US Food and Drug Administration (FDA) in 2016 and remains the only FDA-approved medication available to treat hallucinations and delusions associated with PDP. However, pimavanserin can increase QTc interval by approximately 5– 8 ms. The potential for QTc prolongation should be considered in patients with symptomatic cardiac arrhythmias and those receiving QT-prolonging medications. In choosing a medication to treat PDP, expected efficacy must be balanced with potential safety concerns for individual patients.

Keywords: QTc interval prolongation, antipsychotic agents, clozapine, quetiapine, pimavanserin

Introduction

Parkinson’s disease (PD) is classically characterized by motor features related to central nervous system degeneration.1 Although motor symptoms are central to the diagnosis of PD, it is now recognized as a motor and nonmotor systemic illness with involvement of the autonomic nervous system and multiple major neurotransmitter systems in the brain. Nonmotor manifestations include autonomic dysfunction and neuropsychiatric symptoms (NPS), which may manifest at any stage but are particularly prevalent in advanced PD.2,3 The causes of both autonomic dysfunction and NPS are multifactorial, include disease-specific neurodegeneration, and can be exacerbated by treatments for PD.4–7

Approximately 70%–80% of people with PD experience central and peripheral autonomic dysfunction, which can affect the cardiac sympathetic and parasympathetic systems.8–10 Myocardial denervation has been observed in patients early in the course of PD disease and can lead to corrected QT interval (QTc) prolongation.11 Prolongation occurs regardless of comorbidities or coadministration of QTc-prolonging medications9,12 and appears to worsen with PD severity and age.13 QTc prolongation >500 ms is particularly dangerous, as it can lead to arrhythmias, including Torsade de pointes (TdP), which is associated with sudden cardiac death.14

PD-related NPS include anxiety, depression, agitation, aggression, and psychosis.3,5 NPS are caused by alterations to a variety of neurotransmitters such as dopaminergic, serotonergic, noradrenergic, and cholinergic signaling.5 PD psychosis (PDP) affects more than 20% of all patients with PD and up to 70% of those with advanced PD.6,15 The hallucinations and delusions that occur with PDP are typically visual, stemming from changes in dopaminergic and serotonergic pathways, including upregulation of 5-HT2A signaling.16 Auditory, olfactory, and tactile hallucinations may also manifest as the disease progresses.6,7 PDP symptoms may be experienced as threatening or nonthreatening and add to patient distress and caregiver burden, such that their occurrence is a common reason for nursing home admission.17–19 Due to the lack of effective treatment options for PDP, symptom management has traditionally involved reducing the dosage of medication used to treat Parkinsonism (eg, levodopa) at the cost of the motor benefits associated with the medication. That, however, is not always practical because of exacerbation of motor symptoms. Therefore, treatment often involves managing cholinergic deficit and serotonergic dysfunction by adding a new medication as needed to alleviate remaining psychotic symptoms.6,15 Quetiapine has been the drug of choice in the past, despite a paucity of evidence supporting its use.

Although only pimavanserin is currently approved to treat hallucinations and delusions associated with PDP,20 a variety of antipsychotics (eg, quetiapine, clozapine, and risperidone), acetylcholinesterase inhibitors (eg, donepezil, galantamine, rivastigmine), or the N-methyl-D-aspartate (NMDA) receptor antagonist memantine are commonly used (Table 1).20–29 Data are inconsistent regarding the effects of antipsychotics on QTc interval prolongation.30–32 Some studies suggest that antipsychotics and antidementia therapies have no or minimal cardiac effect, others show clinically significant changes in QTc interval, and still others have attributed effects on QTc interval to polypharmacy or cardiac comorbidities.31,33,34

Table 1 Medications Commonly Used to Treat Parkinson’s Disease Psychosis (Name, Disease State Studied, Evidence of QT Interval Prolongation >500 ms, Increase in QT Interval from Baseline)

A common mechanism by which drugs prolong the QTc interval includes blocking potassium channels encoded by the human ether-A-go-go-related gene (hERG), which drives cardiac and neuronal cell repolarization.35,36 Antipsychotics, including aripiprazole, clozapine, olanzapine, pimavanserin, quetiapine, and risperidone, have been shown to be able to block or inhibit these channels in vitro.35,37–39 Acetylcholinesterase inhibitors (eg, donepezil, galantamine, rivastigmine) can affect heart function by increasing acetylcholine levels, thereby activating cardiac acetylcholine receptors, which in turn open voltage-gated calcium channels to increase intracellular calcium, which can prolong the QTc interval.40,41 Memantine blocks NMDA receptors, which when activated in the heart promote cardiac cell apoptosis and oxidative stress, and promote development of ventricular arrhythmias.42 Thus, memantine’s primary effect on the heart would be expected to be cardioprotective. However, some reports have suggested that memantine treatment could promote adverse cardiovascular events in some patients, though the mechanisms at play are unclear.43,44 Given these potential mechanisms of QTc prolongation and the risk for QTc interval prolongation in older patients with PD, we reviewed the literature to better understand the relative prolongation induced by therapies commonly used in real-world settings to treat PDP.

Literature Search

PubMed and Embase databases were searched for English-language publications with available full text. No date restrictions were set. A search of titles and abstracts was conducted in December 2019 and January 2020. Both atypical antipsychotics and dementia medications regularly used to treat psychosis in people with PD were included in the search. The search string used the following terms: “QT interval prolongation” AND “aripiprazole OR clozapine OR olanzapine OR pimavanserin OR quetiapine OR risperidone OR donepezil OR galantamine OR memantine OR rivastigmine.”

The authors assessed the titles and abstracts of search results for eligibility, and full text was obtained for all potentially relevant articles. Publications were included in the literature review if they described findings related to QTc interval among adults receiving at least 1 antipsychotic or dementia treatment of interest. Systematic reviews and meta-analyses, prospective, retrospective, and observational studies, and case reports were included. Reports or studies in patients <18 years of age were excluded, as were reports of QTc interval prolongation following overdose and congenital long QT syndrome. Narrative review articles, preclinical studies, disease management guidelines, conference abstracts, and correspondence were also excluded. Study results and details from case reports regarding medication effects on QTc interval were extracted from all articles meeting the inclusion criteria.

Of the 463 publications returned by the database searches, 90 had available full text, met the eligibility criteria, and were included in the literature review. Due to the stringency of our search criteria, some publications that reported QTc prolongation may have been missed. In particular, the authors were aware of 2 additional relevant articles not included in the search results that presented sufficient value to be included in this review. These articles described cardiac safety (including effects on QTc interval) in patients receiving clozapine45 and donepezil.46 The literature review, therefore, included 12 systematic reviews or meta-analyses (Table 2), 54 prospective or retrospective studies (Table 3), and 26 case reports (Table 4).

Table 2 Systematic Reviews and Meta-Analyses

Table 3 Prospective, Retrospective, Observational Studies

Table 4 Case Reports and Case Series

The definition of QTc prolongation varied across publications. Some studies and case reports considered prolongation to occur at ≥500 ms, whereas others used lower limits (eg, >450–470 ms), and still others referred to the magnitude of increase from baseline (eg, >60 ms).

Antipsychotics

Most publications reported on multiple antipsychotics rather than assessing the effects of a single drug and evaluated treatments in people with schizophrenia, not PDP. The magnitude of effect on QTc interval and risk of prolongation >500 ms varied across antipsychotics and between studies. Analyses reported a 0.4-ms reduction in QTc interval with aripiprazole and a 3- to 6-ms increase with quetiapine, olanzapine, and risperidone,31 with quetiapine and olanzapine associated with increases greater than those with risperidone (P < 0.01).47 In contrast, 1 study found no QTc prolongation with olanzapine, quetiapine, or risperidone,48 with similar rates of change in QTc interval among these 3 medications (−0.0099 to 0.0030 ms/day).49

Many factors can affect a patient’s QTc intervals, including cardiac and hepatic comorbidities, use of QTc-prolonging medications, older age, female sex, and time of day.50–52 The choice of antipsychotic may contribute to 17%–55% of a patient’s response, with 10%–12% of this variation attributed to genetic expression.53

In general, QTc prolongation appears to occur infrequently with atypical antipsychotics. A search of the World Health Organization pharmacovigilance database found that, as of January 2010, 489 reports exist on QT prolongation, TdP, and/or cardiac arrest related to olanzapine, and 520 reports exist on QT prolongation, TdP, and/or cardiac arrest related to quetiapine since the medication approvals in 1996 and 1995, respectively.54 Analysis of a database encompassing Austria, Germany, and Switzerland reported a QTc prolongation frequency of 0.006% among patients treated with clozapine or quetiapine and 0% with aripiprazole, olanzapine, and risperidone.55

Aripiprazole

Aripiprazole was mentioned in 6 systematic reviews and meta-analyses,30,31,56–59 13 prospective or observational studies,33,47,55,60–69 and 4 case reports.70–73 The literature consistently showed that aripiprazole is associated with small reductions in QTc interval. Four meta-analyses of aripiprazole described reduced mean QTc intervals (−0.43 to −3.38 ms) and reduced risk of prolongation with aripiprazole when compared with placebo (risk ratios [RR], 0.33 [95% confidence interval (CI), 0.12–0.93] to 7.58 [0.40–143.03]; Table 2).30,31,56,58

Six studies of 1351 patients with psychiatric disorders reported no clinically significant QTc interval prolongation with aripiprazole (Table 3).60,62,63,65,66,74 These findings were supported by a cross-sectional study that controlled for patient age, sex, diagnosis, length of illness, setting (inpatient vs outpatient), use of mood stabilizers or antidepressants, number of antipsychotics, and antipsychotic dose.33 In that study, aripiprazole was associated with a reduced risk of QTc interval prolongation in contrast to other drugs (P = 0.013), whereas no significant effect was observed with clozapine, olanzapine, quetiapine, or risperidone. Case reports of patients receiving aripiprazole were consistent with findings from the meta-analyses and clinical studies (Table 4).70,73

The product label for aripiprazole lists QT prolongation as a rare event, occurring in fewer than 1 in 1000 patients.21 The evidence for QTc interval reduction with aripiprazole, plus its mechanism of action as a dopamine receptor blocker and agonist, would count in its favor as a treatment for PDP. However, aripiprazole is associated with worsened motor function in PD and, therefore, is not recommended for PDP.75,76

Clozapine

The effect of clozapine on QTc interval was described in 1 systematic review,59 13 studies,33,45,50,51,55,61,67,77–82 and 6 case reports.71,73,83–86 One study found no significant change from baseline in mean QTc interval or the incidence of QTc prolongation,79 but this is inconsistent with findings from other researchers. Four studies of 4951 psychiatric inpatients have reported an increased risk of QTc prolongation with clozapine (odds ratios, 1.006 [95% CI, 1.003–1.008] and 2.4 [95% CI, 1.4–4.2]), with the magnitude of effect being dose dependent (Table 3).45,50,51,82

Case reports also reported heterogeneous effects of clozapine. A 37-year-old woman who experienced QTc prolongation (an increase from 458 to 508 ms) with risperidone 1–2 mg/day had no such response with clozapine (dose not specified; Table 4).71 On the other hand, QTc intervals of 472–504 ms have been reported in men ages 30–45 years taking clozapine 100–400 mg/day.73,84,86 In each case, QTc returned to baseline after switching to aripiprazole, quetiapine, or olanzapine.

The label for clozapine warns about the risk of QTc prolongation,22 but the risk appears to be dose dependent,45,50 and patients with PDP require doses 10-fold lower (6.25–50 mg/day) than those used to treat schizophrenia.6,75 However, it is important to keep in mind that because the effect is dose-dependent, even a dose that would on its own not cause a significant effect could interact with other QTc-modifying factors (eg, concomitant medication with QTc prolongation effects, age, comorbidities) to cause clinically significant QTc prolongation.50–52

Because clozapine does not worsen motor function, it has been used to treat PDP. Long-term treatment with clozapine, however, can cause autonomic dysfunction, including increased heart rate and reduced heart rate variability. Autonomic dysfunction is already a concern in PD, and it further increases the risk of QTc prolongation.77 Also, clozapine is associated with agranulocytosis, though the risk is dose dependent and usually avoided in patients with PD if low doses are used. Finally, severe neutropenia (neutrophil count <0.5 × 103/μL) has been reported in 0.91% of patients treated with clozapine.6,75 As a result, weekly blood count monitoring is required during the first year of treatment, which increases the burden for patients and caregivers.6,75

Olanzapine

Olanzapine was mentioned in 6 systematic reviews and meta-analyses,30,31,56,57,87,88 26 studies,32,33,47–49,52–55,61,64,67–69,77,78,80,81,89–96 and 4 case reports.83,97–99 Multiple meta-analyses and clinical studies reported no or minimal effect of oral olanzapine on QTc interval,88,89,91 with a placebo-adjusted standardized mean difference of −0.14 ms30 and 1.7-ms increases from baseline.91 Intramuscular olanzapine reduced QT interval by approximately 3 ms during the 24 hours post injection.30,88,89,94 Any QTc effects may be sex-specific: in a study by Suzuki et al,47 women who received olanzapine experienced longer mean QTc intervals than men (P = 0.007), whereas such differences were not observed with other antipsychotics (Table 3).

Case reports of patients receiving polypharmacy who had prolonged QTc intervals described no cardiac effects of olanzapine (Table 4).83,97–99 To our knowledge, the only exception reported is that of an elderly woman with a QTc prolongation triggered by the addition of the CYP450 inhibitor ciprofloxacin to an established regimen of olanzapine, valsartan, and azathioprine.100

The product label for olanzapine does not warn of QTc effects and reports no significant differences in comparison with placebo in the proportions of patients experiencing clinically important QT changes.25 Despite the reported cardiac safety of olanzapine, the medication is ineffective in treating psychotic symptoms in PDP and affects motor function;6,75,76 it therefore is not recommended in this patient population.

Pimavanserin

No studies of pimavanserin were identified in our literature search. However, the product label for pimavanserin advises that the medication prolongs the QT interval.20 Although clinical trials for pimavanserin were not identified in the literature search, QT interval prolongation was mentioned in the publications of these trials.101–104 In a Phase 3 study of patients with PDP, pimavanserin was associated with a mean 7.3-ms increase in Bazett’s-corrected QTc interval over 6 weeks, in comparison with no change for placebo.102 During the open-label extension (OLE) of this study, 12 (2.6%) patients experienced individual events of a Fridericia-corrected QTc interval >500 msec, and 6 (1.3%) patients experienced an adverse event of prolonged QT interval.104 In the 12-week Phase 2 trial of pimavanserin in patients with Alzheimer’s disease, those who received pimavanserin had a mean 9.4-ms increase in Fridericia-corrected QTc interval from baseline, in comparison with a decrease of 2.0 ms for placebo.101 One patient in each treatment group had a change from baseline of ≥60 ms, recorded at day 15 for both. In the 12-week open-label period of a Phase 3 trial of pimavanserin in patients with dementia-related psychosis, including patients with Parkinson’s disease dementia, pimavanserin was associated with a mean Fridericia-corrected QTc prolongation of 5.4 msec, with 1 (0.3%) patient experiencing an increase in QTc of ≥60 ms.103 In all studies, the effect of pimavanserin on QTc interval was not associated with related adverse events.101–104 In 2019, the authors performed a retrospective review of medical records for 48 patients treated with pimavanserin in their movement disorders clinic, with the goal of determining whether their electrocardiograms showed any evidence of QTc abnormalities. No QTc prolongation was identified for any of the 48 patients (data on file).

Pimavanserin is currently the only antipsychotic approved by the US Food and Drug Administration (FDA) for the treatment of hallucinations and delusions associated with PDP.20 The product label warns about the increased risk of QTc prolongation.20 Pimavanserin is recommended for patients with PDP who do not have preexistent QTc prolongation and are not taking QTc-prolonging medications.20 A recent OLE safety study demonstrated the long-term safety and tolerability of pimavanserin specifically in patients with PDP, showing that types of adverse events reported in an OLE study were comparable to the 6-week placebo-controlled studies.104 Patients were excluded if they received other medications known to prolong the QT interval, or had a baseline Bazett-corrected QT interval of >460 for males or >470 for females.104

Quetiapine

Quetiapine was mentioned in 4 systematic reviews and meta-analyses,30,31,57,87 25 studies,33,47–49,53–55,64,67–69,78,80,81,91,92,96,105–112 and 8 publications describing case reports.72,113–119 A Cochrane meta-analysis reported no significant difference in risk of QTc prolongation between quetiapine and comparator antipsychotics, but RRs (95% CIs) favored comparator drugs: aripiprazole, 3.21 (95% CI, 0.13–76.74); olanzapine, 12.96 (95% CI, 0.73–229.17); and risperidone, 1.34 (95% CI, 0.36–5.04) (Table 2).87 Quetiapine was associated with a 4.81-ms (95% CI, 0.34–9.28) greater increase in QTc interval than was olanzapine, with similar QTc effects as for risperidone.87 The results from individual studies were heterogeneous, with some studies48,111,112 showing minimal or no effect on QTc interval and others91,106,108 suggesting that quetiapine is associated with mean or median changes from baseline of −5 to +20 ms (Table 3). A mean change in QTc interval of −0.5 ± 17.9 ms was observed with quetiapine doses of 400–600 mg/day, but in the same study, 9.6% of patients had increases in QTc interval >20 ms in relation to baseline.111 In other studies of psychiatric patients, quetiapine was associated with QTc prolongation of 1.3–5.7 ms in relation to baseline.69,91,112 In healthy volunteers, quetiapine elicited mean QTc interval increases of 10.2 ms, with prolongation occurring in a dose-dependent manner.108

The product label for quetiapine states that QTc effects were not observed in clinical trials but postmarketing reports suggest that prolongation can occur in the context of overdose, comorbidity, and coadministration of QTc-prolonging medications.29 Quetiapine does not appear to worsen extrapyramidal symptoms. However, orthostatic hypotension and somnolence are commonly reported adverse events and may lead to falls because of its properties as an alpha-1 adrenergic and histamine H1 antagonist.29 In addition, randomized controlled trials have not consistently shown efficacy in reducing psychosis symptoms in this patient population.6,75,76

Risperidone

Risperidone was mentioned in 10 systematic reviews and meta-analyses,30,31,56,57,59,87,120–123 28 studies,32–34,47–53,55,60,61,64,67–69,80–82,91,92,124–129 and 2 case reports.71,130 Risperidone generally elicited minimal changes in QTc interval, although interpatient and interstudy variability were observed (Tables 2 and 3). Whereas 1 study identified QTc increases from baseline of up to 12 ms with 3–8 mg/day risperidone,126 other studies found no significant effect on QTc interval.32,129 A Cochrane meta-analysis reported a greater risk of prolonged QTc intervals in patients receiving risperidone versus placebo.123

In healthy individuals, the QTc interval follows a circadian pattern, being slightly prolonged (approximately 5 ms) at night in relation to daytime. Risperidone appears to exaggerate this pattern (approximately 14 ms prolongation), whereas olanzapine does not.52

As with olanzapine, the product label for risperidone does not warn of QTc effects and reports no significant differences in comparison with placebo in the proportions of patients experiencing clinically important QT changes.24,25 However, risperidone should be avoided for PDP because of the increased risk of extrapyramidal symptoms.6,75,76

Dementia Therapies

A retrospective cohort study of Medicare claims between 2006 and 2014 examined cardiovascular events for patients treated with memantine monotherapy, acetylcholinesterase inhibitor monotherapy (ie, donepezil, rivastigmine, galantamine), or a combination of memantine and acetylcholinesterase inhibitor.131 QTc interval prolongation was reported for 0.1%−0.2% of all patients, with no difference between monotherapy and combination therapy. The risk of QTc interval prolongation was also similar between acetylcholinesterase inhibitor and memantine monotherapies and between combination therapy and memantine monotherapy.

Donepezil

The effect of donepezil on QTc interval was mentioned in 3 studies46,67,131 and 7 case reports of 8 patients.119,132–137 The prospective studies identified no significant changes from baseline in the QTc intervals of elderly individuals with Alzheimer’s disease receiving donepezil 5–10 mg (Table 3).46,131 In contrast, a database analysis reported that donepezil, but not antipsychotics or galantamine, was associated with greater odds of long QT syndrome (LQTS) in comparison with other adverse events, with a median 14 days to onset of LQTS.67 Seven case reports (n = 8) published between 2007 and 2019 described QTc intervals of 463 to 777 ms,119,132–137 including 4 cases of TdP and 1 instance of TdP without QTc prolongation (433 ms) (Table 4).132,133,135,136 The product label for donepezil does not mention QTc effects in the context of normal (ie, non-overdose) use.6,138

Galantamine

Two studies67,131 and 1 case report139 described QTc prolongation during galantamine treatment (Table 3). One study identified a 0.2% rate of QTc prolongation.131 In the case report, QTc prolongation (503 ms) occurred in an elderly man who restarted galantamine after a 2-week interruption.139 QTc interval had shortened to 443 ms within 4 days of discontinuing the second round of galantamine (Table 4). Similar to the donepezil label, the galantamine label does not mention effects on QTc during normal use.27

Memantine

Two studies131,140 mentioned the effects of memantine on QT interval (Table 3). In the first, 2 (5%) patients with Alzheimer’s disease who received memantine 20 mg/day plus citalopram 30 mg/day experienced QTc interval prolongation, whereas no prolongation was observed in patients who received memantine alone.140 The second study showed that 0.1% of Medicare patients who received memantine experienced QTc interval prolongation.131

Rivastigmine

Only 1 study assessed the effects of rivastigmine on QTc interval, reporting a 0.01% incidence of QTc prolongation with rivastigmine in patients with Alzheimer’s disease (Table 3).131 As with other dementia therapies, the product label for rivastigmine does not mention the drug’s effects on QTc in the context of normal use.23 However, the FDA did not specifically examine QTc prolongation at the time of approval.

Discussion

Psychosis can occur at any stage of PD and is often treated with antipsychotics or dementia medications. Given the motor and nonmotor features of PD, general patient characteristics (eg, older, with comorbidities), and heterogeneous effects of antipsychotics and dementia therapies, the optimal PDP medication has been unclear.6 Dementia therapies are generally preferred for treating cognitive impairment, despite a lack of studies supporting their efficacy for treating hallucinations and delusions associated with PDP. Antipsychotics such as aripiprazole, olanzapine, and risperidone affect motor function and should be avoided in people with PD.

Clinicians must balance the expected benefits with the potential harms when selecting the appropriate medication from the remaining options, clozapine, pimavanserin, and quetiapine. For example, clozapine can reduce PDP symptoms but is associated with dose-dependent QTc interval prolongation45,50,51,82 and autonomic dysfunction, which is already a concern in PD and further increases the risk of QTc prolongation.77 Furthermore, the requirement for ongoing weekly blood draws to monitor for neutropenia and agranulocytosis adds substantial patient and caregiver burden.6,75 Quetiapine has not shown efficacy in treating PDP6,75,76 and is not recommended for patients with comorbidities or who receive concomitant QT-prolonging drugs owing to possible prolongation.29,91,106,108 Quetiapine can also exacerbate underlying fatigue and cause sedation and orthostatic hypotension, all of which may potentially increase the risk of falling.29 Pimavanserin was approved by the FDA in April 2016 and is the only medication approved to treat hallucinations and delusions associated with PDP, but it should be avoided in patients with risk factors for prolonged QT interval or who receive QT-prolonging medications.20 Pimavanserin has been shown to increase QTc interval by approximately 5–8 ms.20,102

As PD progresses, therapeutic options may become increasingly limited due to comorbidities and other medications the patient requires; this may coincide with further development of non-motor symptoms that require treatment. Patients with advanced PD frequently present with multiple risk factors for QTc prolongation or the need for medications that cause QTc prolongation that may interact, such as older age and cardiac comorbidities. In such patients, treatments may include an antipsychotic for psychosis, an acetylcholinesterase inhibitor for apathy, domperidone for orthostatic hypotension, or citalopram for depression. The Movement Disorder Society’s (MDS) treatment guidelines caution that citalopram poses a risk for QTc prolongation in older adults, especially at higher doses, and domperidone requires electrocardiogram (ECG) monitoring due to its known association with ventricular tachyarrhythmia and sudden cardiac death in PD patients.141 While MDS guidelines state that acetylcholinesterase inhibitors do not require specialized monitoring, they do acknowledge that these medications could affect the patient’s ECG,141 and the American Geriatrics Society advises caution when combining acetylcholinesterase inhibitors with antipsychotics that affect blood pressure.142 It is critical that the physician considers these effects before prescribing these medications to avoid an interaction that produces clinically significant QTc prolongation.

While we pursued a broad review of the literature, some reports may have been excluded due to restrictions that we placed on the search. In particular, conference abstracts can report current analyses that could include data of QTc prolongation with the medications that we examined. Due to the inconsistent and limited availability of conference abstracts and lack of peer review, we considered these abstracts outside of the scope of this review. Additionally, our search terms required mention of “QT interval prolongation,” which could have excluded some publications that reported QTc prolongation using alternative terms or phrases such as “QT prolongation” or “arrhythmia.”

The magnitudes of QT interval prolongation in the studies included in this review were relatively small (often 5–10 ms), and the clinical importance of small changes in the QT interval has not been determined. QTc prolongation >500 ms, which has been associated with a risk of TdP, is generally rare with antipsychotics and dementia treatments.54,55 The risk of QTc prolongation is increased with the presence of autonomic dysfunction, comorbidities (eg, heart disease, congestive heart failure, myocardial infarction, left ventricular dysfunction, arrhythmia, liver disease, septic shock, thyroid disease), electrolyte imbalance, polypharmacy, increased age, female sex, and genetic variation.12,51,53,117,122,130,143,144 Symptomatic cardiac arrhythmias, congenital QT interval prolongation, hypomagnesemia, and hypokalemia are particular risk factors for further QT prolongation. In the PD population, autonomic dysfunction, comorbidities (eg, heart, liver, or endocrine conditions), polypharmacy, and older age are common,12,145–147 and PD occurs at a slightly higher frequency in males than females (1.6:1).148

Potential therapies to treat PDP should be considered in the context of other drugs that a patient is receiving for comorbidities to avoid the potential for additive effects of multiple QT-prolonging medications. Drug classes associated with QT interval prolongation include Class 1A or Class 3 antiarrhythmics (eg, quinidine, procainamide, amiodarone, sotalol); antibiotics such as gatifloxacin and moxifloxacin; the antipsychotics ziprasidone, chlorpromazine, and thioridazine; and others (eg, pentamidine, levomethadyl acetate, methadone).20,29 Also, because most medications included in this review are metabolized by the CYP450 system, coadministration with CYP450 metabolic inhibitors can theoretically increase plasma concentrations of 1 or more of these agents, increasing the risk for cardiotoxicity.91,100,117,130 In clinical studies, metabolic inhibitors appear not to influence QTc interval in patients receiving olanzapine, quetiapine, or risperidone,91,112 but they can interact with clozapine.22 Some authors have also suggested that dose, which is often elevated in patients who require polypharmacy, may play a larger role than polypharmacy in QTc prolongation.33,45,50,51,78 Most QTc data from this review were from patients with schizophrenia, who require higher antipsychotic doses than do patients with PDP to alleviate symptoms of psychosis. The use of lower doses for PDP might, therefore, be associated with a reduced risk of QTc prolongation in this patient population.

Clinicians should take care when evaluating QT intervals, to avoid unnecessarily discontinuing useful medications. Although Bazett’s formula is commonly used to calculate QTc, it can lead to overcorrection and misunderstanding of the true cardiac effects of medications.149 This was demonstrated in a case in which a patient receiving clozapine 400 mg/day had a resting heart rate of 80 beats per minute and QTc values of 508 ms (Bazett’s), 484 ms (Fridericia), 479 ms (Framingham), and 475 ms (Hodges).85 Many publications in our review did not report the formula used, and of those that did, Bazett’s was more common than Fridericia. In the study by Nielsen et al,111 QT intervals were corrected with both Fridericia’s and Bazett’s formulas. Whereas the Fridericia formula showed a mean QTc change from baseline of −0.5 ms ± 17.9 ms with quetiapine, Bazett’s formula suggested that QTc interval increased by 7.9 ms ± 21.9 ms. Because of the tendency to overcorrect the QT interval, Bazett’s formula is not recommended by the American Heart Association for electrocardiogram calculations.149

The risk of QT interval prolongation should be evaluated for an individual patient with PD in the context of selecting an appropriate therapy but should not prevent initiating a treatment for hallucinations and delusions. The presence of psychosis in patients with PD has been associated with increased caregiver burden,19 nursing home placement,18 and mortality,17 indicating a need for timely implementation of an effective treatment strategy.

Importantly, none of the publications described in this review were specifically conducted in patients with PDP. Most studies of antipsychotics were done in patients with schizophrenia or other psychiatric disorders, and most studies of antidementia treatments were done in patients with Alzheimer’s disease. Though some characteristics may overlap between patients with PDP and patient populations in these studies, risk factors for medication-related cardiac effects may be more common in certain patient populations than in others. For example, increased age and polypharmacy might increase the risk of QTc prolongation in patients with PDP, and these factors may influence treatment decisions. Clinical trials are therefore needed to determine the QTc-prolonging effects of each drug in this unique patient population. Despite the recent requirements set forth by some insurance companies, mandating electrodiagnostic testing before starting a single drug may not be necessary because there is not a clear consensus on the effect of most of these medications on QTc prolongation.

Conclusions

In general, second-generation antipsychotics are associated with small changes in QTc interval, and pathological QTc prolongation and TdP are rare. The potential for QTc prolongation, however, is important to consider in patients with symptomatic cardiac arrhythmias and those receiving QT-prolonging medications. In choosing a medication to treat PDP, the expected efficacy must be balanced by possible safety concerns for individual patients.

Symptoms of PDP need to be treated and a patient’s risk of QT interval prolongation should factor into treatment choice with what is known about medication efficacy and other safety concerns. Pimavanserin is the only FDA-approved treatment for hallucinations and delusions associated with PDP. Clozapine is also effective but can cause (or exacerbate) autonomic dysfunction and requires frequent blood monitoring throughout treatment. The efficacy of quetiapine has not yet been proven in PDP, and other antipsychotics are generally ineffective in PDP or negatively affect motor function. Although clinicians may prescribe acetylcholinesterase inhibitors in the setting of PDP with cognitive impairment, to date, clinical trials have not demonstrated their efficacy in treating specific symptoms of psychosis. Studies are needed that compare the effects of antipsychotics on QT interval in patients with PDP.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

Funding for medical writing and editorial support was provided by Acadia Pharmaceuticals Inc. Alison Adams, PhD (Ashfield MedComms, an Ashfield Healthcare company), provided writing support based on input from authors, and Dena McWain (Ashfield MedComms) copyedited and styled the manuscript per journal requirements.

Disclosure

Yasar Torres-Yaghi serves as speaker and advisor for Acorda Therapeutics Inc., Acadia Pharmaceuticals Inc., Amneal Pharmaceuticals Inc., AbbVie Inc., Abbott Laboratories, Sunovion Pharmaceuticals Inc., and Teva Pharmaceutical Industries Ltd.; advisor for KeifeRx LLC; and speaker for Teva Pharmaceutical Industries Ltd. and US WorldMeds LLC. Amelia Carwin serves as advisor for Acadia Pharmaceuticals Inc. and Kyowa Kirin Co. Ltd. Jacob Carolan has no conflict of interest to report. Steven Nakano serves as advisor for Acadia Pharmaceuticals Inc. and Kyowa Kirin Co. Ltd. Fahd Amjad serves as consultant for Teva, Acadia, Lundbeck, Amneal, AbbVie, Kyowa Kirin, Neurocrine, and Sunovion, outside the submitted work. Fernando Pagan serves as speaker and consultant for Acorda Therapeutics Inc., Acadia Pharmaceuticals Inc., Adamas Pharmaceuticals, Amneal Pharmaceuticals Inc., AbbVie Inc., Abbott Laboratories, Kyowa Kirin Co. Ltd., Merz Pharma GmbH & Co. KGaA, Sunovion Pharmaceuticals Inc., Teva Pharmaceutical Industries Ltd., and US WorldMeds LLC; is founder of and advisor for KeifeRx LLC; and receives research funding from NIH/NIA, Sun Pharmaceutical Industries Ltd., and Alzheimer’s Research Foundation. The authors report no other conflicts of interest in this work.

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