Do long-acting injectable antipsychotics have a higher risk of QTc prolongation than immediate-acting antipsychotics?

Introduction
The availability of long-acting injectable (LAI) antipsychotic formulations provides an option for continuous drug exposure that may improve drug adherence compared with daily immediate-acting oral antipsychotics in patients with schizophrenia or bipolar disorder.1,2 In the United States, there are 6 antipsychotic medications currently available as LAIs: aripiprazole, fluphenazine, haloperidol, olanzapine, paliperidone, and risperidone.

The use of any antipsychotic agent is associated with risks that clinicians should monitor.1 For example, antipsychotic medications can cause electrocardiographic (ECG) changes, including increased heart rate, ST segment depression, and prolongation of QT and PR intervals. The prolongation of the corrected QT (QTc) interval is clinically relevant, as it is associated with ventricular arrhythmias, including torsade de pointes, which can be fatal. The risk of QTc prolongation differs between agents, but the risk for arrhythmia increases when the QTc interval ≥500 ms or is 60 ms above the baseline QTc. Based on this risk threshold, it is recommended to discontinue a medication associated with QTc prolongation if the interval consistently exceeds 500 ms.

With increasing use of long-acting injectable antipsychotics, there is concern surrounding the withdrawal of the drug in case of an adverse event, including prolonged QTc interval. This article focuses on determining if there is a higher risk of QTc prolongation with LAI antipsychotics compared to immediate-acting antipsychotics.

Long-acting injectable antipsychotics and electrocardiogram data
Many of the LAIs contain relevant data comparing the injectable formulations to immediate-acting formulations or placebo with regards to ECG changes within their package inserts.2,3 Table 1 summarizes the relevant information available from the package inserts. Other package inserts (aripiprazole ER/lauroxil, haloperidol decanoate, Uzedy [risperidone ER]) stated that QTc prolongation have been reported, but this appears to be based on all drug studies (oral/immediate release included), not specific to LAI formulations. The package insert for fluphenazine decanoate has no mention of any studies related to QT prolongation with any formulation.4

Table 1. Relevant package insert data on ECG changes with injectable formulations.5-11
Drug Study design and durationa Relevant resultsOther considerations
Olanzapine pamoate (Zyprexa Relprevv)5Comparison of olanzapine pamoate LAI vs oral olanzapine in a 24-week studyNo significant differences on ECG changes between groupsNA
Paliperidone palmitate, 4-week dosing (Erzofri ER, Invega Sustenna)6,7Fixed-dose studies: Four efficacy studies of Invega Sustenna in patients with schizophrenia and long-term study in patients with schizoaffective disorder

Maintenance study in patients with schizophrenia		Fixed dose studies: No participant experienced a change in QTcLD >60 ms and no participant had a QTcLD value >500 ms at any time.

Maintenance study: No participant had a QTcLD change >60 ms; one participant had a QTcLD of 507 ms (QTcB = 483 ms)		In a QT study of oral paliperidone, the 8 mg dose of IR oral paliperidone (n=50) showed a mean increase from baseline in QTcLD of 12.3 ms on day 8 at 1.5 hours post-dose.

The mean CmaxSS (113 ng/mL) was more than 2-fold the exposure observed with the max recommended 234 mg maintenance dose of another once monthly paliperidone ER injectable administered in the deltoid (predicted median CmaxSS=50 ng/mL)
Paliperidone palmitate, 12-week dosing
(Invega Trinza)8		Long-term maintenance trial of Invega Trinza in patients with schizophreniaQTcLD >60 ms was observed in 1 patient (<1%) in the OL phase

No patient had an increase in QTcLD >60 ms after treatment in the DB phase

No patient had QTcLD >480 ms at any point during the trial		In a QT study of oral paliperidone, the 8 mg dose of IR oral paliperidone (n=50) showed a mean increase from baseline in QTcLD of 12.3 ms on day 8 at 1.5 hours post-dose

The mean CmaxSS (113 ng/mL) was approximately 2-fold the exposure observed with the max recommended 819 mg dose of Invega Trinza administered in the deltoid (predicted median CmaxSS=56 ng/mL)
Paliperidone palmitate, 6-month dosing (Invega Hafyera)9DB, AC, randomized study of Invega Hafyera in patients with schizophrenia during the DB phaseQTcLD >60 ms was observed in 1 patient (60 ms after treatment in the DB phase

No patient had QTcLD >480 ms at any point during the trial		In a QT study of oral paliperidone, the 8 mg dose of IR oral paliperidone (n=50) showed a mean increase from baseline in QTcLD of 12.3 ms on day 8 at 1.5 hours post-dose

The mean CmaxSS (113 ng/mL) was approximately 1.3-fold the exposure observed with the max recommended 1560 mg dose of Invega Hafyera administered in the gluteal muscle (mean CmaxMD=89.3 ng/mL)
Risperidone microspheres (Rykindo ER microspheres) for IM injection10A 12-week DB, PC trial
in patients with schizophrenia treated with 25 mg or 50 mg risperidone LAI (n=202) or placebo (n=98)

A 24-month DB, PC trial in patients with bipolar I disorder (N=227)

A 52-week DB, PC trial in patients with bipolar disorder (N=85)		No significant differences in QTc intervals (using Fridericia’s and linear correction factors) between groups in any study or patient populationNA
Risperidone ER (Perseris) for subcutaneous injection118-week DB, PC study

12-month, long-term safety study		No clinically relevant differences in QTc intervals (using Fridericia’s and linear correction factors) between groups in any study or with any studied doseNA
a Not all sample sizes were reported.
Abbreviations: AC=active-controlled; CmaxMD=maximum dose peak plasma concentration; CmaxSS=steady-state peak plasma concentration; DB=double-blind; ECG=electrocardiogram; ER=extended-release; IM=intramuscular; IR=immediate-release; LAI=long-acting injectable; NA=not applicable; OL=open-label; PC=placebo-controlled; PP3M=every-three month paliperidone palmitate injectable suspension; QTcB=Bazett’s QT corrected interval; QTcLD=QT interval corrected for heart rate using the population specified linear derived method.

Additional literature
There is limited additional data outside of studies and evidence included in package inserts. One 2022 meta-analysis by Schneider-Thoma et al evaluated the efficacy and tolerability of 32 oral and LAI antipsychotics.12 For outcomes specific to QT prolongation, 13 studies with 10 antipsychotics (n=2982), including aripiprazole and paliperidone LAIs, were included in meta-analysis. There was no significant difference in QTc interval with aripiprazole LAI (mean difference [MD], -3.07 ms; 95% credible interval [CrI], -9.24 to 3.02) or paliperidone LAI (MD, 2.01 ms; 95% CrI, -2.56 to 6.61) compared to placebo. There were no comparisons of LAI to immediate-acting formulations. Another meta-analysis by Ostuzzi et al (2021) found that paliperidone palmitate 3-month formulation had a lower risk of QTc prolongation than paliperidone palmitate 1-month formulation based on a pairwise meta-analysis of 1 study.13 There were no meta-analyses comparing LAI formulations to immediate-release formulations or placebo.

Conclusion
Based on limited evidence from package inserts and meta-analyses, there appears to be no clinically relevant difference in QTc prolongation between LAI and immediate-release formulations among antipsychotic agents.

References

  1. Crismon ML, Tawny L, Buckley PF. Schizophrenia. In: DiPiro JT, Yee GC, Haines ST, Nolin TD, Ellingrod VL, Poley L. eds. DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. McGraw Hill; 2023:chap 87. Accessed April 18, 2025. https://accesspharmacy.mhmedical.com/content.aspx?sectionid=267918845&bookid=3097
  2. Drugs@FDA: FDA-approved drugs. U.S. Food & Drug Administration. 2025. Accessed April 18, 2025. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm
  3. DailyMed. National Library of Medicine. 2025. Accessed April 25, 2025. https://dailymed.nlm.nih.gov/dailymed/index.cfm
  4. Fluphenazine decanoate. Package insert. Hikma Pharmaceuticals USA, Inc.; 2025.
  5. Zyprexa Relprevv. Package insert. Eli Lilly and Company; 2023.
  6. Erzofri Extended-Release. Package insert. Shandong Luye Pharmaceutical Co., Ltd.; 2024.
  7. Invega Sustenna. Package insert. Janssen Pharmaceuticals, Inc.; 2025.
  8. Invega Trinza. Package insert. Janssen Pharmaceuticals, Inc.; 2025.
  9. Invega Hafyera. Package insert. Janssen Pharmaceuticals, Inc.; 2025.
  10. Rykindo Extended-Release Microspheres. Package insert. Shandong Luye Pharmaceutical Co., Ltd.; 2025.
  11. Perseris. Package insert. Indivior Inc.; 2025.
  12. Schneider-Thoma J, Chalkou K, Dörries C, et al. Comparative efficacy and tolerability of 32 oral and long-acting injectable antipsychotics for the maintenance treatment of adults with schizophrenia: a systematic review and network meta-analysis. Lancet. 2022;399(10327):824-836. doi:10.1016/S0140-6736(21)01997-8
  13. Ostuzzi G, Bertolini F, Del Giovane C, et al. Maintenance treatment with long-acting injectable antipsychotics for people with nonaffective psychoses: a network meta-analysis. Am J Psychiatry. 2021;178(5):424-436. doi:10.1176/appi.ajp.2020.20071120

Prepared by:
Rachel Brunner, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

May 2025

The information presented is current as of April 18, 2025. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.