by Samara White, PharmD; Tammie Lee Demler, PharmD, MBA, BCGP, BCPP; and Eileen Trigoboff, RN, PMHCNS-BC, DNS, DABFN

Drs. White and Demler are with The New York State Office of Mental Health at Buffalo Psychiatric Center in Buffalo, New York. Drs. Demler and Trigoboff are with the State University of New York at Buffalo School of Pharmacy and Pharmaceutical Sciences, Department of Pharmacy Practice in Buffalo, New York, and the State University of New York at Buffalo School of Medicine, Department of Psychiatry in Buffalo, New York.

FUNDING: No funding was provided for this article.

DISCLOSURES: The authors declare no conflicts of interest relevant to the content of this article.

Innov Clin Neurosci. 2025;22(4–6):14–19.

Abstract

Objective: Psychiatric inpatients often require complex medication regimens due to the refractory nature of their serious mental illness (SMI) and the high prevalence of medical comorbidities. Among the many inherent issues associated with these regimens are the potential pharmacodynamic drug interactions resulting in an increased risk of QTc prolongation and the potential sequelae, Torsades de Pointes (TdP). This study builds on previous research that demonstrated the utility of the MedSafety Scan (MSS) clinical decision support (CDS) tool by establishing theoretical evidence from patients with SMI but did not provide objective data to validate its use in this population. This has left prescribers questioning whether the MSS CDS tool is capable of accurately guiding prescribing decisions in this vulnerable patient population. Therefore, the objective of this study was to assess the degree of correlation between psychiatric patients’ QTc intervals and their MSS-calculated TdP risk scores to objectively validate the predictive impact and clinical value of the MSS tool in psychiatric inpatients for the purpose of informing safe prescribing. Methods: A retrospective analysis was conducted to assess the relationship between participants’ MSS TdP risk scores and their QTc Δ, defined as the difference between participants’ measured QTc intervals and sex-specific QTc prolongation thresholds (female individuals: 470ms; male individuals: 450ms). The MSS TdP risk score is calculated based on patient demographic data, medical diagnoses, serum electrolyte values, and medications. Data from 251 subjects were extracted from an adult inpatient psychiatric facility’s electronic medical record system from February 1, 2018, through November 30, 2023. Inpatients with a documented electrocardiogram during the study period were eligible for inclusion, and the exclusion criterion was having a Criminal Procedure Law (CPL) designation. Data were analyzed using a one-way analysis of variance (ANOVA) with alpha set to 0.01. Results: The data from the ANOVA that compared participants’ QTc Δ to MSS TdP risk score were found to be significant (p<0.01). Conclusion: This study showed that the MSS CDS tool accurately reflected the relationship between our psychiatric inpatients’ measured QTc intervals and their predicted MSS TdP risk scores, which objectively validated the predictive impact and clinical utility of this tool in our psychiatric population. Prescribers can use this tool to mitigate QTc prolongation risk for patients without underlying, unknown congenital risk; therefore, this can be an important course of action in treating psychiatric patients, given their predisposition to decreased lifespans and their increased risk of QTc prolongation due to SMI-related proarrhythmic factors. The MSS tool is an open-source, web-based CDS tool that provides comprehensive analyses of TdP risk, drug interactions, and duplicate therapies, and produces a detailed patient-specific report that allows for documentation of management plans. These features prove MSS to be a valuable tool for psychiatric inpatient clinicians to establish an initial basic clinical impression to advise need for additional comprehensive medical follow-up, cardiology consultation, or pharmacotherapeutic modifications.

Keywords: QTc interval, QTc prolongation, Torsades de Pointes, clinical decision support tool, MedSafety Scan, antipsychotics, antidepressants

Psychiatric inpatients frequently require complex medication regimens due to the refractory nature of serious mental illness (SMI) and prevalence of chronic medical comorbidities.^1–4 Among the many inherent issues with prescribing such regimens are the potential pharmacodynamic consequences of these combinations, such as QTc interval prolongation and the potential sequelae, Torsades de Pointes (TdP).^1,3–8 Psychiatric medications, especially antipsychotics and antidepressants, are some of the most commonly implicated agents in QTc prolongation.^6,9,10 In fact, of the 315 medications currently listed in the Arizona Center for Education and Research on Therapeutics (AzCERT) CredibleMeds QTdrugs database of medications that contribute to risk of developing TdP, over 70 are psychiatric medications, agents used to treat substance use disorder (SUD), or for management of extrapyramidal symptoms (EPS).¹¹ Psychiatric agents can prolong the QTc interval by up to about 30 to 40ms in addition to naturally occurring daily QTc interval fluctuations, which vary by about 76 to 102ms on average.^10,12,13 People experiencing SMI have an increased risk of QTc prolongation and progression to TdP compared to the general population due to many additional factors. First, drug-drug interactions (DDIs) are major contributors and as would be expected, risk of DDIs increase with higher pill burdens.^14,15 

Patients with SMI generally have increased pill burdens for a multitude of reasons, including simultaneous management of mental health and chronic medical conditions, use of polypharmacy for treatment-resistant cases, and prescribing cascades due to undesirable side effects of psychiatric medications.^{2,5,9,15–19} Second, patients with refractory SMI are often treated with doses that exceed United States Food and Drug Administration (FDA)–approved maximum daily doses, which is concerning considering the dose-dependent nature of QTc prolongation for most agents.^{8,10,18,20,21} Third, structural and functional cardiovascular disease (CVD) are major proarrhythmic factors, and patients with SMI have exceptionally higher incidences of CVD than the general population and subsequently twice the mortality risk.^4,18,22,23 Additional risk factors of QTc prolongation include, but are not limited to, age of 65 years or older; female sex; hepatic or renal dysfunction; electrolyte disturbances, specifically hypocalcemia, hypomagnesemia, and hypokalemia; family history of sudden cardiac death; and illicit substance use.^24–28

The normal QTc interval range is 360 to 470ms for female individuals and 350 to 450ms for male individuals; intervals that exceed these ranges are considered prolonged. For every 10ms the QTc interval is prolonged, the risk of developing TdP increases approximately 5 to 7 percent.^14,19,29 Although no exact threshold of prolongation guarantees the development of TdP, QTc intervals of 500ms or greater are considered abnormal, and risk of TdP increases two-to-threefold.^14,17,30 TdP is a rare but life-threatening condition; the mortality rate is about 10 to 25 percent, and a study by Gibbs et al³¹ showed that roughly 50 percent of patients with at least one recording of a QTc interval of 500ms or greater died within 3.6 years.^29,31–33 Given that people experiencing SMI have reduced life expectancies by up to 25 years as compared to the general population, the mortality risks from prolonged QTc intervals and TdP are extremely concerning.^{3,23,25,34,35} While many factors contribute to the life expectancy disparity between populations, such as higher rates of smoking and polysubstance use, sedentary lifestyle, poor nutritional status, medical comorbidities, and incidence of sudden cardiac death (SCD), the complicity of medication regimens and resulting adverse drug events (ADEs) are often overlooked, especially QTc prolongation.^3,4,35–39

Historically, it has been challenging for clinicians to identify patients who are at risk of QT prolongation; this might be due to lack of knowledge or familiarity with QTc prolongation risk factors, lack of experience with electrocardiogram (EKG) interpretation, information overload, or prioritizing other clinical matters.^4,8,26,41 Adding to these obstacles, the lack of consensus in monitoring and managing QTc prolongation might dissuade clinicians from identifying patients who are at risk in the first place.²¹ Efforts by pharmacists and health informatic systems to notify prescribers of QTc prolongation risks have largely been dismissed due to alert fatigue from the overwhelming frequency or prescriber perceptions that alerts are inconsequential.^40,41 Unfortunately, this pattern precipitates inadvertent ADEs and increases risk of patient morbidity and mortality. Conversely, FDA boxed warnings for QTc prolongation with citalopram and ziprasidone have increased hesitancy to initiate psychiatric agents and promoted conservative dose escalation practices for some prescribers.²¹ Although this might prevent QTc prolongation, these prescribing practices can disadvantage patients by not optimizing therapeutic management of clinical symptoms.²⁴ The challenge of preserving both patient safety and medication optimization highlight the importance of supporting prescribers in a manner that adequately conveys the magnitude and urgency of patient QTc/TdP risks.⁴⁰ Reliable clinical support tools, such as MedSafety Scan (MSS), can convey these risks and might consequently encourage conscious, safe, and effective prescribing habits.

MSS is an open-source, web-based, clinical decision support (CDS) tool that calculates an algorithmic, patient-specific TdP risk score that can be used to empower clinicians and improve patient outcomes by informing safe prescribing practices. The MSS TdP risk score quantifies the degree to which patients are at risk of developing TdP by analyzing both their demographic and medication information. MSS is hosted by Arizona Center for Education and Research on Therapeutics’s (AzCERT’s) CredibleMeds and is accessible via https://www.medsafetyscan.org/. The integration of MSS with CredibleMeds’ QTdrugs database allows the MSS algorithm to calculate the risk of QTc prolonging medications based on classification as “known risk,” “possible risk,” or “conditional risk” of developing TdP. The MSS TdP risk score algorithm is based on the Tisdale Risk Score (TRS) which has been clinically validated to calculate a QTc prolongation score in intensive care unit (ICU) settings.^19,33,41 To calculate TdP risk in non-ICU settings, the MSS CDS tool modified risk factors in the TRS algorithm to capture important data that were not considered in more acute settings. With these modifications, the tool can be calibrated for use in both ICU settings (using the TRS algorithm) and non-ICU/outpatient settings (using the MSS algorithm); a comparison of the algorithms is detailed in Table 1.

Between the two, the MSS algorithm likely calculates a more accurate risk score since the TRS algorithm is limited to only allowing a maximum of two medications in its calculation. Additionally, DDIs are major contributing factors in psychiatric medication–induced QTc prolongation; most studies report that the prevalence of torsadogenic DDIs in people with SMI ranges up to 65 to 95 percent.^9,14,16 MSS’s inclusion of cytochrome P450 (CYP) inhibitors paired with removing the maximum limit of medications in the analysis demonstrates two of many considerable improvements in the algorithm’s capability. Other improvements include the capacity to capture magnesium and calcium serum levels, diagnosis of congenital long QT syndrome, specification of QTc intervals of 500ms or greater, and inclusion of comorbid CVDs, including atrial fibrillation, heart failure, and heart valve disorders. These additions improve the sensitivity of the MSS algorithm and risk score compared to TRS. An additional benefit of MSS over TRS is the stratification of high risk versus very high risk in the risk score interpretation, which is advantageous due to accuracy of patient risk identification. A comparison of the algorithms’ score interpretations is listed in Table 2.^33,41

In addition to QT risk score calculation and analysis, other benefits of the MSS CDS tool include analyses of DDIs ranked by severity, contraindicated drug combinations, and therapeutic duplications. Additionally, the MSS tool provides a section where users can document a patient-specific management plan by toggling checkboxes for ordering an EKG, considering alternative medications, checking electrolytes, reducing the dose of medications with QTc/TdP risk, requesting cardiology consultation, and a free-text section for further documentation. All MSS documentation and analyses are included in summarized patient reports, which can be stored under Health Insurance Portability and Accountability Act (HIPAA)–compliant MSS online patient profiles, and PDF reports can be printed, filed, or shared with clinical team members.⁴¹ Through using MSS, assessing medication regimens no longer has to be a cumbersome task for clinicians that might have formerly impeded quantity or quality of care. MSS is considered to be a practical CDS option that provides an initial risk analysis that can be confirmed with additional follow-up when clinically indicated.

Previous research has proven the utility of the MSS CDS tool by establishing theoretical evidence from psychiatric patients but has not provided objective data to validate its use in this population.²⁵ This gap has left prescribers questioning whether the tool is capable of accurately guiding prescribing decisions in this vulnerable patient population. Accordingly, the objective of this study was to assess the degree of correlation between QTc intervals and MSS-calculated TdP risk scores among patients with SMI to objectively validate the predictive impact and clinical value of the MSS CDS tool in psychiatric inpatients for the purpose of informing safe prescribing.

Methods

This study was approved by the New York State Office of Mental Health’s Institutional Review Board. A retrospective analysis was conducted to assess the relationship between participants’ MSS TdP risk score and their QTc Δ, defined as the difference between participants’ measured QTc intervals and sex-specific QTc prolongation thresholds (female individuals: 470ms; male individuals: 450ms). The MSS TdP risk score is calculated based on patient demographic data, medical diagnoses, serum electrolyte values, and medications. The MSS TdP risk score algorithm is detailed in Table 3.

Data from 251 subjects were extracted from a New York state adult psychiatric inpatient facility’s electronic medical record (EMR) system from February 1, 2018, through November 30, 2023. All adult inpatients who had an EKG in the EMR during the study period were eligible for inclusion, and the exclusion criterion was having a Criminal Procedure Law (CPL) designation. Data were analyzed using a one-way analysis of variance (ANOVA) with MSS risk score as the independent variable and QTc Δ as the dependent variable. Alpha was set to 0.01, and the 99-percent confidence interval (CI) was two-sided.

Results

Out of the 321 participants screened for this study, 251 met the inclusion criteria. The data from the ANOVA that compared QTc Δ to MSS risk score were found to be significant (p<0.01) for all participants (Table 4). Other participant study data can be found in Table 5.

Discussion

The data from our study showed that the MSS CDS tool accurately reflected the relationship between patients’ measured QTc intervals and their MSS TdP risk scores. Previous research on the MSS tool lacked objective evidence from psychiatric patients; consequently, it was uncertain if the calculated MSS risk score could be applied in this population. This study objectively validates the use of the MSS tool in psychiatry to establish initial clinical impressions; therefore, clinicians can more confidently address QTc challenges when prescribing decisions must be navigated.

Previous research conducted by Demler and O’Donnell²⁵ revealed that although a high number of alerts cautioning of QTc prolongation risk might be warranted as a responsible pharmacovigilance practice, the actual incidence of high-risk MSS QTc scores in the inpatient psychiatric setting might be surprisingly low. Notably, however, high-risk MSS scores are likely to be a reliable prognostic indicator of problematic prolongation. Therefore, pharmacy implementation of MSS TdP scoring might assist in the medication management process by reducing QTc prolongation alert fatigue and by preventing clinical inertia, both of which result in suboptimal clinical efficacy.^21,42,44 Utilization of MSS scoring in psychiatric clinical practice is optimally conducted prior to initiating medications that might potentiate cumulative risks, especially in the setting of additional nonmedication risk factors. However, the utility of MSS remains evident even after regimens have been established for prescribers to make informed, rational deprescribing decisions for the purpose of risk reduction. While data analyzing pharmacy-driven implementations of QTc prolongation monitoring protocols have been positive, future studies should conduct similar analyses using the MSS CDS tool on a large scale to confirm both patient safety outcomes and prescriber acceptance and to evaluate more critically any emergence of outliers with scores that do not align with their actual measured QTc interval.^43–46

Although efforts to mitigate QTc prolongation will always be considered good clinical practice and are in the best interest of the patient, it is necessary to address rising conflicting views regarding psychiatric medication QTc/TdP risks. Some research has shown that although the magnitude of psychiatric-induced QTc prolongation has been verified, the clinical significance and the risk of TdP development is insignificant.^{10,13,17,18,24,47,48} Clinically significant prolonged QTc intervals induced by psychiatric medications are likely consequential to an individual’s intrinsic variability and presence of additional risk factors.^10,17,18,49 Despite the conflicting evidence behind the impact of psychiatric agents on TdP risk, the consensus is that prescribers should continue to recognize and identify patients’ QTc/TdP risk factors, as this will distinguish vulnerable patients who would benefit from more conservative prescribing practices.¹⁷

Limitations. This study had five limitations. The first limitation was that only scheduled medications were used in MSS analyses and as needed (PRN) medications were excluded. Psychiatric inpatients utilize QTc-prolonging PRN medications on a regular basis, such as antipsychotics for agitation or irritability and hydroxyzine for sleep. The exclusion of these medications could have led to lower MSS risk scores; however, this data was excluded because the high variability of PRN medication use would potentially compromise data by overestimating patients’ use of those medications.

Similarly, the second limitation is the binary inclusion strategy for collection of medication data rather than data that reflected actual medication intake—if the scheduled medication was prescribed, it was utilized in the assessment. This strategy might have overinflated MSS scores compared to analyses that account for medication refusals. However, we felt that it was appropriate to use this model of inclusion because it is often the case that inpatients who refuse their medications also refuse EKG collection; therefore, by the standards of our study inclusion criteria, these patients would not have been eligible for participation.

The third limitation of this study is that participants’ medication data were captured on the same day that EKGs were performed, which only provides a snapshot of the regimens. As such, there is a possibility that the captured QTc interval might not accurately reflect the impact of dose changes, discontinuations, or new additions that occurred shortly before the EKG was conducted since it can take several days for agents to affect the QTc interval.^48,50 However, it is our opinion that the medication data that we used for this study was appropriate for the scope of this project.

The fourth limitation of this study is that emerging research has challenged the widely accepted notion that QTc prolongation is the best clinical marker of TdP development. Instead, computer-based models have demonstrated that architectural changes in the right slope of T-waves have a much stronger correlation to development of TdP than QTc prolongation.^17,24 However, we did not consult EKG morphology experts or software and only had objective values for the following EKG features: ventricular rate, PR interval, QRS duration, QT/QTc interval, and P, R, and T axes. Because of this, the QTc interval was the best clinical marker available for this study. Future studies can take all four of these limitations into account to build upon our foundation of research.

The fifth limitation is that electrolyte values were not available for all patients included in our study unless there was a diagnosis of abnormality. Since there were no diagnosed electrolyte abnormalities in our study cohort, we did not include electrolyte values in our MSS risk score calculations. 

Regarding limitations of the MSS CDS tool, one apparent flaw is that medication doses and pharmacokinetic factors, such as smoking or smoking cessation, which can affect drug concentrations, are not considered in the analysis. This can lead to inaccurate MSS risk scores, since QTc prolongation is dose-dependent in most cases and since smoking induces CYP1A2, a metabolic pathway that is common for many torsadogenic and/or narrow therapeutic index medications, such as asenapine, clomipramine, clozapine, and olanzapine.^{8,10,18,20,51} Furthermore, there are reports that up to half of the most implicated medications in TdP are not captured in CredibleMeds’ QTdrugs database.²⁹ This negatively affects the accuracy of MSS’s predictive impact and might also lead to an artificially low risk score. CredibleMeds provides a disclaimer that their tool is not intended to provide medical advice and/or treatment.

Conclusion

In pursuit of reducing the risk of medication-induced QTc interval prolongation and TdP in psychiatric patients, we sought to validate a clinical decision support tool that quantifies patients’ TdP risk status. With the objective validation of the MSS TdP risk score in patients with SMI, prescribers can more confidently tailor medication regimens to mitigate QTc prolongation risk, an important course of action in treating psychiatric patients given their predisposition to decreased lifespans and their increased risk of QTc prolongation due to complex medication regimens and other SMI-related proarrhythmic factors. Although no CDS is without flaw or weakness, the MSS tool is valuable for clinicians practicing in psychiatric inpatient settings.

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