A 2023 review provides an overview of current literature discussing use of antipsychotic medications in the context of delirium-related agitation and risk of QTc prolongation. In addition to medications, several modifiable risk factors may impact incidence of QTc prolongation, including electrolyte abnormalities, renal dysfunction, and drug-drug interactions. Non-modifiable risk factors that are associated with increased risk include age > 65 years, female sex, medical conditions including cardiac disease, and other medical conditions. Atypical antipsychotics commonly used for management of delirium in the intensive care unit include olanzapine, quetiapine, risperidone, and ziprasidone; most agents appear to be associated with some degree of QT risk. Olanzapine is associated with mild to moderate increases in QTc interval, with data indicating 4.29 msec of prolongation. While the extent of prolongation appears to be comparable to risperidone and quetiapine based on some studies, incidence of QTc prolongation is reported to be less likely with olanzapine. Quetiapine, considered a low-potency second-generation antipsychotic, is associated with mixed safety data regarding QTc prolongation. Studies have demonstrated increases ranging from 1.3 to 10.2 msec following quetiapine use; in 2011 the FDA issued a warning related to risk of QTc prolongation in events of overdose or use in patients with significant risk factors. Yet, other studies have suggested inconsequential impact of quetiapine on QTc interval. Overall data are inconclusive, but quetiapine is considered to be moderately associated with QTc prolongation in patients without significant risk factors. Risperidone, which exhibits behavior comparable to typical antipsychotics, is associated with a moderate degree of QTc prolongation, with studies finding prolongation of 3.9 to 4.77 msec. Risk with risperidone appears to be more pronounced in patients with other risk factors, while use is considered to be relatively safe in patients without risk factors for QTc prolongation or Torsade de Pointes. Finally, of atypical antipsychotics, ziprasidone has been found to have the most significant QTc prolongation, with studies demonstrating an increase ranging from 9.6-15.0 msec. Per an FDA warning, ziprasidone should be discontinued in patients with persistent QTc measurements > 500 msec and use is contraindicated in patients with significant risk of prolongation. A summary of QTc prolongation risk for the discussed antipsychotics is presented in Table 1. [1]
The degree of QTc prolongation associated with various oral antipsychotic drugs was investigated in a 2019 systematic review and meta-analysis. Of the 402 total studies included in the meta-analysis, 51 studies (N= 15,467 patients) provided relevant data regarding QTc prolongation. While the incidence rate and risk of prolongation with each agent was not evaluated, the extent of prolongation was compared. Lurasidone and partial dopamine agonists were associated with the least degree of QTc prolongation, while sertindole was associated with the most. In order of least to greatest extent of QTc prolongation, antipsychotics were listed as follows, with corresponding mean difference in msec change in QTc: lurasidone (-2.21), brexpiprazole (-1.46), cariprazine (-1.45), aripiprazole (-0.43), placebo (0; reference), paliperidone (1.21), haloperidol (1.69), quetiapine (3.43), olanzapine (4.29), risperidone (4.77), asenapine (5.60), iloperidone (6.93), ziprasidone (9.70), amisulpride (14.10), and sertindole (23.90). Confidence in evidence was highly variable across individual medications; data for lurasidone, brexpiprazole, cariprazine, and aripiprazole was considered to be low, while haloperidol was very low. Data regarding all other agents was considered to be of moderate or high confidence. [2]
A 2022 pharmacovigilance study employs a disproportionality analysis to investigate the risk of reporting QTprolongation between 20 antipsychotics. The study included data from 1967 to 2019, stored in the Global Individual Case Safety Reports database maintained by the World Health Organization. When comparing antipsychotics, 3 first-generation (pimozide, zuclopenthixol, haloperidol) and 5 second-generation (sertindole, ziprasidone, amisulpride, iloperidone, quetiapine) antipsychotics showed a statistically significant increase in the likelihood of reporting QT prolongation. Following sertindole, ziprasidone and amisulpride were the medications with the greatest reporting odds ratios (ROR; see Table 2). The lowest ROR was associated with lurasidone. Compared to second-generation antipsychotics, first-generation antipsychotics were linked to a higher QT prolongation reporting risk (ROR 1.21; 95% confidence interval [CI] 1.10 to 1.33). RORs for QT prolongation and affinity for the hERG channel were shown to be positively correlated in a statistically nonsignificant way (R2= 0.14, Pearson coefficient= 0.41, p= 0.1945). [3]
Previous papers have emphasize that all antipsychotic agents have the potential to prolong the QT interval or cause ventricular repolarization, which can result in Torsades de Pointes and sudden cardiac death. However, this effect is dose-dependent and most pronounced with low-potency first-generation antipsychotics such as chlorpromazine and thioridazine, and second-generation antipsychotics like ziprasidone. [4], [5]
The adverse effects of antipsychotic medications vary widely, ranging from minor tolerability issues such as mild sedation or dry mouth to more severe and potentially life-threatening conditions such as myocarditis and agranulocytosis. Each antipsychotic agent has a distinct adverse effect profile and individuals may react differently to these effects. Please refer to Table 3 for a relative comparison of QTc prolongation risk associated with various antipsychotics. In general, the incidence of adverse effects differs significantly across the various agents, making it challenging to categorize them strictly into first- and second-generation classifications; however, tardive dyskinesia is an exception, being more common with older antipsychotic agents. Notably, different population groups, such as children, adolescents, and the elderly, may experience specific adverse effects more intensely. For instance, youth are more prone to weight gain and sedation, while the elderly are at a higher risk of orthostatic hypotension-related falls and anticholinergic effects (e.g., cognitive impairment). Additionally, individuals may exhibit substantial variations in their susceptibility to adverse effects and how they experience them. These individual variations in susceptibility and responses emphasize the need for tailored approaches in antipsychotic medication management. [6]