First-generation antipsychotics and QTc: any role for mediating variables?

Carrà, Giuseppe; Crocamo, Cristina; Bartoli, Francesco; Lax, Annamaria; Tremolada, Martina; Lucii, Claudio; Martinotti, Giovanni; Nosè, Michela; Bighelli, Irene; Ostuzzi, Giovanni; Castellazzi, Mariasole; Clerici, Massimo; Barbui, Corrado

doi:10.1002/hup.2540

Cited by 27 publications

(14 citation statements)

References 39 publications

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“…25,40,47 A large cross-sectional survey in Italy found that first-generation antipsychotics, age, gender, alcohol misuse, and concurrent risky drugs prolonged QTc interval. 58 In a retrospective review of antipsychotic overdoses, there appeared to be a significant risk of QTc prolongation with amisulpride and thioridazine. 59 These results indicate that use of psychotropic drugs should be undertaken with caution, particularly in patients with other risk factors for QTc prolongation.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of ECG abnormalities and risk factors for QTc interval prolongation in hospitalized psychiatric patients

Ansermot

Bochatay

Schlapfer

et al. 2019

Therapeutic Advances in Psychopharmacology

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Background: Psychiatric patients are at risk of cardiovascular diseases, and many psychotropic drugs can prolong QTc interval. Requirements for electrocardiogram (ECG) monitoring have been set up in our psychiatric university hospital. The objective of this study was to determine the proportion of adult patients who had an ECG during their hospitalization, the prevalence of ECG abnormalities, the evolution of the QTc after admission, and the risk factors for QTc prolongation. Methods: Retrospective analysis of ECGs and clinical data of all patients with a complete hospitalization in 2015. Assessment of the influence of covariates on QTc using linear mixed-effects models. Results: At least one ECG ( n = 600) was performed during 37.6% of the stays ( n = 1198) and in 45.5% of the patients ( n = 871). Among the patients with an ECG, 17.9% had significant ECG abnormalities, including 7.6% with a prolonged QTc. QTc measured at admission and during hospitalization did not change significantly ( n = 46, 419.4 ± 29.7 ms, 417.2 ± 27.6 ms, p = 0.71). In the multivariate model (292 patients, 357 ECGs), the covariates significantly associated with the QTc were gender (+15.9 ms if female, p < 0.0001), age (+0.4 ms/year, p = 0.0001), triglyceride levels (+5.7 ms/mmol/l, p = 0.005), and drugs with known risk of torsades de pointes (+6.2 ms if ⩾1 drug, p = 0.028). Conclusions: The prevalence of hospitalized psychiatric patients with an abnormal ECG indicates that ECGs should be performed systematically in this population. Prescription of psychotropic drugs should be done cautiously, particularly in patients with QTc prolongation risk factors.

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Section: Discussionmentioning

confidence: 99%

Prevalence of ECG abnormalities and risk factors for QTc interval prolongation in hospitalized psychiatric patients

Ansermot

Bochatay

Schlapfer

et al. 2019

Therapeutic Advances in Psychopharmacology

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“…The data of this report originate from a multicenter cross-sectional survey that has recently been described in detail. 17 – 19 In brief, the study recruited 2558 patients with psychiatric illnesses in Italy from 35 psychiatric services participating in the STAR (Servizi Territoriali Associati per la Ricerca) Network. During a three-month recruitment period, all adult inpatients and outpatients were included if they had full mental capacity, gave written informed consent, and if an ECG was recorded during the hospital stay (inpatients) or during the recruitment period (outpatients).…”

Section: Methodsmentioning

confidence: 99%

Combinations of QTc-prolonging drugs: towards disentangling pharmacokinetic and pharmacodynamic effects in their potentially additive nature

Meid

Bighelli

Mächler

et al. 2017

Therapeutic Advances in Psychopharmacology

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Background:Whether arrhythmia risks will increase if drugs with electrocardiographic (ECG) QT-prolonging properties are combined is generally supposed but not well studied. Based on available evidence, the Arizona Center for Education and Research on Therapeutics (AZCERT) classification defines the risk of QT prolongation for exposure to single drugs. We aimed to investigate how combining AZCERT drug categories impacts QT duration and how relative drug exposure affects the extent of pharmacodynamic drug–drug interactions.Methods:In a cohort of 2558 psychiatric inpatients and outpatients, we modeled whether AZCERT class and number of coprescribed QT-prolonging drugs correlates with observed rate-corrected QT duration (QTc) while also considering age, sex, inpatient status, and other QTc-prolonging risk factors. We concurrently considered administered drug doses and pharmacokinetic interactions modulating drug clearance to calculate individual weights of relative exposure with AZCERT drugs. Because QTc duration is concentration-dependent, we estimated individual drug exposure with these drugs and included this information as weights in weighted regression analyses.Results:Drugs attributing a ‘known’ risk for clinical consequences were associated with the largest QTc prolongations. However, the presence of at least two versus one QTc-prolonging drug yielded nonsignificant prolongations [exposure-weighted parameter estimates with 95% confidence intervals for ‘known’ risk drugs + 0.93 ms (–8.88;10.75)]. Estimates for the ‘conditional’ risk class increased upon refinement with relative drug exposure and co-administration of a ‘known’ risk drug as a further risk factor.Conclusions:These observations indicate that indiscriminate combinations of QTc-prolonging drugs do not necessarily result in additive QTc prolongation and suggest that QT prolongation caused by drug combinations strongly depends on the nature of the combination partners and individual drug exposure. Concurrently, it stresses the value of the AZCERT classification also for the risk prediction of combination therapies with QT-prolonging drugs.

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“…164 The effect on QTc is not peculiar to clozapine; it is often seen with other antipsychotics, especially FGAs, and other psychiatric drugs. [165][166][167] Almost all of the drugs known to prolong the QT interval both directly or through one of their metabolites seem to preferentially block the rapid component of the delayed rectifier outward K+ current, IKr, of an ion channel in ventricular cardiomyocytes, whose α subunit is encoded by the human ethera-go-go related gene (HERG). 168 Clozapine has demonstrated the capability to block HERG currents and this may account for drug-induced QT prolongation.…”

Section: Uncommon Adverse Effectsmentioning

confidence: 99%

Safety of antipsychotics for the treatment of schizophrenia: a focus on the adverse effects of clozapine

Berardis¹,

Rapini²,

Olivieri³

et al. 2018

Therapeutic Advances in Drug Safety

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125

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Clozapine, a dibenzodiazepine developed in 1961, is a multireceptorial atypical antipsychotic approved for the treatment of resistant schizophrenia. Since its introduction, it has remained the drug of choice in treatment-resistant schizophrenia, despite a wide range of adverse effects, as it is a very effective drug in everyday clinical practice. However, clozapine is not considered as a top-of-the-line treatment because it may often be difficult for some patients to tolerate as some adverse effects can be particularly bothersome (i.e. sedation, weight gain, sialorrhea etc.) and it has some other potentially dangerous and life-threatening side effects (i.e. myocarditis, seizures, agranulocytosis or granulocytopenia, gastrointestinal hypomotility etc.). As poor treatment adherence in patients with resistant schizophrenia may increase the risk of a psychotic relapse, which may further lead to impaired social and cognitive functioning, psychiatric hospitalizations and increased treatment costs, clozapine adverse effects are a common reason for discontinuing this medication. Therefore, every effort should be made to monitor and minimize these adverse effects in order to improve their early detection and management. The aim of this paper is to briefly summarize and provide an update on major clozapine adverse effects, especially focusing on those that are severe and potentially life threatening, even if most of the latter are relatively uncommon.

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First-generation antipsychotics and QTc: any role for mediating variables?

Abstract: Our findings showed that FGAs, concurrent risky drugs, and alcohol use disorders prolonged QTc. FGAs had a direct effect on QTc, confirming the need for clinicians to monitor a risk that could lead to sudden unexplained death. Copyright © 2016 John Wiley & Sons, Ltd.

Cited by 27 publications

References 39 publications

Prevalence of ECG abnormalities and risk factors for QTc interval prolongation in hospitalized psychiatric patients

Prevalence of ECG abnormalities and risk factors for QTc interval prolongation in hospitalized psychiatric patients

Combinations of QTc-prolonging drugs: towards disentangling pharmacokinetic and pharmacodynamic effects in their potentially additive nature

Safety of antipsychotics for the treatment of schizophrenia: a focus on the adverse effects of clozapine

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