Is the QTc-prolonging effect of mirtazapine dose-related?

Comment by InpharmD Researcher

According to one pharmacokinetic analysis, there appeared to be a positive correlation between mirtazapine concentrations and QTc prolongation; however, the highest dose used was above the typical recommended dose in clinical practice and the degree of QTc prolongation was not deemed to be clinically meaningful. Evidence, mostly from retrospective studies, showed minimal risk of QTc prolongation with mirtazapine use but data on direct comparisons between lower and higher doses is limited.

Background

A 2014 review evaluated the potential for QT prolongation with nonselective serotonin reuptake inhibitor (non-SSRI) antidepressants. The antidepressants reviewed included bupropion, desvenlafaxine, duloxetine, levomilnacipran, mirtazapine, venlafaxine, and vilazodone. In regards to mirtazapine, data from the package insert and correspondence provided by the drug manufacturer indicated that QTc prolongation has been reported in patients taking mirtazapine; however, details of these cases were not provided. In the electrocardiogram (ECG) safety analysis of 338 patients treated with mirtazapine versus 261 patients who received placebo, no clinically significant QTc prolongation events were observed with mirtazapine (mean QTc increase of 1.6 ms in mirtazapine group and no QTc interval exceeding 500 ms). Two articles reported the impact of mirtazapine overdose on ECG results. The first, a retrospective chart review (N= 29), found no patient had a significantly prolonged QT/QTc in those admitted to a toxicology unit for mirtazapine overdose (mean dose 594 mg). The second, an observational case series of mirtazapine overdoses (N= 267; 89 with single-agent mirtazapine ingestion and 178 with mirtazapine and concomitant medication), also found no reports of arrhythmias or QT prolongation; all ingestions were of doses >120 mg of mirtazapine, with the median ingested dose of 420 mg. The authors concluded that available reviews show minimal risk for QT prolongation with mirtazapine use, including in overdose; however, further randomized controlled trials with similar baseline characteristics are needed to fully evaluate the risk of QT prolongation associated with mirtazapine. [1]

A 2020 qualitative narrative review summarized the known cardiovascular side effects of newer antidepressants. The recommended use, dosing-ranges, cardiovascular effects, and general advantages and disadvantages of 12 non-selective serotonin reuptake inhibitors (SSRIs) were discussed, including, venlafaxine, desvenlafaxine, duloxetine, milnacipran, levomilnacipran, mirtazapine, bupropion, vilazodone, vortioxetine, agomelatine, moclobemide, and ketamine/esketamine. A 2002 randomized, controlled trial (N= 255) that compared mirtazapine at doses ranging from 15 to 45 mg per day compared to paroxetine in adults ≥ 65 years old with depression over 16 weeks found no clinically significant changes in electrocardiogram (ECG) from baseline in the mirtazapine group or compared to the paroxetine group. Within the MIND-IT trial, a nested randomized control trial (N= 331) evaluated the efficacy and safety of mirtazapine 15 to 45 mg per day over 24 weeks in adults hospitalized with a myocardial infarction who also had depression. No differences were found in change in QTc interval with mirtazapine compared to placebo. In addition, a retrospective cohort study (N= 61) evaluated the effect of mirtazapine on sudden cardiac death and ECG changes in hospitalized patients who received mirtazapine after a psychiatric consultation. Mirtazapine was initiated at an average dose of 9.8 mg per day and titrated to a mean dose of 13.5 mg per day; no significant changes from baseline ECG parameters and no cardiac events were observed. The authors concluded that mirtazapine seems to be associated with minimal cardiovascular adverse effects in patients who are older, hospitalized, or have cardiovascular disease; however, the studies consist of small numbers of patients with short duration of follow up (up to 24 weeks). [2]

References:

[1] Jasiak NM, Bostwick JR. Risk of QT/QTc prolongation among newer non-SSRI antidepressants. Ann Pharmacother. 2014;48(12):1620-1628. doi:10.1177/1060028014550645
[2] Behlke LM, Lenze EJ, Carney RM. The Cardiovascular Effects of Newer Antidepressants in Older Adults and Those With or At High Risk for Cardiovascular Diseases. CNS Drugs. 2020;34(11):1133-1147. doi:10.1007/s40263-020-00763-z
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Is the QTc-prolonging effect of mirtazapine dose-related?

Please see Tables 1-2 for your response.

 

Mirtazapine's Effect on the QT Interval in Medically Hospitalized Patients

Design

Retrospective Cohort

N=475

Objective

To more thoroughly characterize the QT interval (QTc) changes for medical inpatients started on mirtazapine, a secondary analysis was conducted in the retrospective cohort of 475 patients.

Study Groups

 Mirtazapine group (n= 61)

Inclusion Criteria

Hospitalized patients, received at least one dose of mirtazapine during hospitalization 

Exclusion Criteria

Psychiatric inpatient setting

Methods

Electrocardiogram (ECG) data from at least 1 ECG was performed within 3 days of initial consult and another ECG within 6 days after initiation with the goal of having a baseline and comparator when mirtazapine was almost at steady state. Rhythm interpretations were reviewed for new ventricular tachycardia, torsades de pointes (TdP), and sudden cardiac death.

Duration

Trial Duration: January 2010 to June 2015

Follow-up: 9 days

Outcome Measures

Primary Outcomes: QTc changes, adverse cardiac outcomes

Baseline Characteristics

  

Mirtazapine Group (n= 61)

Age, years

 64.5 ± 14.3

Initial Dose (mg)

 9.8 ± 3.6

Maximum Dose (mg)

 13.5 ± 6.3

# concomitant QTc prolonging medications

 3.2 ± 1.9

Results

Endpoint

Mirtazapine Group (n= 61)

Change in QTc, ms

 -0.31 ± 36.62

Average first QTc, ms

 468.57 ± 42.52

Average second QTc, ms

 468.26 ± 37.56

Number of patients with >20 ms increase in QTc

 15

Number of patients with >40 ms increase in QTc

 6

Number of patients with second QTc >500 ms

 9

Adverse Events

No incidental cases of ventricular tachycardia, TdP, or sudden cardiac death were found

Study Author Conclusions

These data add to the literature supporting the safety of mirtazapine in medically hospitalized patients as no incidental cases of ventricular tachycardia, TdP, or sudden cardiac death were found. Even though the average QTc was greater than 460 ms, the average change in QTc was close to zero.

InpharmD Researcher Critique

This retrospective study had a small sample size and very short follow-up which did not allow for titration of higher doses to be evaulated. The small cohort and retrospective nature of the study also may have contributed to the not clinically significant difference in these study results. However, this did support that intial low-dose of mirtazapine may not cause immediate significant changes to the QTc.



References:

Allen ND, Leung JG, Palmer BA. Mirtazapine's effect on the QT interval in medically hospitalized patients. Ment Health Clin. 2020;10(1):30-33. Published 2020 Jan 9. doi:10.9740/mhc.2020.01.030

 

A Study to Assess the Proarrhythmic Potential of Mirtazapine Using Concentration-QTc (C-QTc) Analysis

Design

Single-center, open-label, multiple-dose, randomized, 3-cohort, placebo- and active-controlled, parallel-group study

N= 54

Objective

To evaluate the effects of mirtazapine on the QTc interval using C-QTc analysis

Study Groups

Mirtazapine (n= 18)

Moxifloxacin (n= 18)

Placebo (n= 18)

Inclusion Criteria

Not explicitly stated 

Exclusion Criteria

Clinically significant medical history, electrocardiogram (ECG) abnormalities, or risk factors for ventricular arrythmias (structural heart disease or cardiac conduction disturbances)

Methods

Participants were randomized into one of the three cohorts and did not participate in any other groups. Mirtazapine dose was gradually titrated to the maximal therapeutic dose of 45 mg/day and to supratherapeutic dose of 75 mg/day. A dose of 30 mg was administered on days 1 to 5, 45 mg on days 6 to 10, 60 mg on days 11 to 15, and 75 mg on days 16 to 20. On days 10 and 20, subjects also received placebo for moxifloxacin to match the study procedures of the other groups. In the moxifloxacin group, participants were given 400 mg as a single dose on day 10 of the trial, followed by an additional 800 mg dose on day 20. A placebo dose was also administered on days 10 and 20; no study drug was administered on days 1 through 9 and 11 through 19. In the placebo group, participants were given placebo doses to match study procedures for the other two groups on days 10 and 20; no study drug was administered on days 1 through 9 and 11 through 19. 

Safety and tolerability was assessed based on reporting of adverse events as well as monitoring of vital signs and laboratory tests. The moxifloxacin group had continuous telemetry performed on day 20 from predose until 24 hours postdose. In all groups, ECG Holter monitor data extractions were obtained on days 10 and 20 within 45 minutes predose, at 0.5, 1, 2, 3, 4, 6, 12 and 24 hours postdose, and at matched times on day -1 within a 5-minute window. 

The prespecified primary analysis was the C-QTc model, which analyzed the relationship between mirtazapine concentrations and baseline-adjusted QTc (ΔQTc); this was performed using a linear mixed-effects model with time point as a fixed effect and plasma concentration as a continuous effect. The upper one-sided 95% CI (equivalent to upper limit of a 2-sided 90% CI) of ΔΔQTc (mirtazapine ΔQTc-placebo ΔQTc) was computed from the model at the observed geometric mean Cmax for the 45 mg and 75 mg mirtazapine doses. The bootstrap resampling technique was used to check the stability and predictability of the model. A similar model was used to analyze the relationship between moxifloxacin concentrations and ΔQTc to ensure assay sensitivity by demonstrating that administration of a single dose of 400 mg moxifloxacin was associated with an increase in QTc interval that is consistent with published literature. 

Duration

June 4, 2015 to August 25, 2015
Outcome Measures

Primary: effect of mirtazapine on QTc interval using C-QTc analysis

Baseline Characteristics

  

Mirtazapine (n= 18)

Moxifloxacin (n= 18)

 Placebo (n= 18)  

Age, mean years

 33.7 ± 10.1 39.3 ± 11 40.4 ± 9  

Female

9 (50%) 9 (50%) 9 (50%)  

White

 18 (100%) 15 (83.3%) 15 (83.3%)  

BMI (mean kg/m2)

 27.1 (23 to 31) 27.3 (22 to 32) 27 (22 to 32)  

Results

Endpoint

 Mirtazapine 45 mg

Mirtazapine 75 mg

Moxifloxacin 400 mg

Moxifloxacin 800 mg

C-QTc Analysis (Plasma Concentration and QTcP Change from Baseline)

Geometric mean Cmax (ng/mL)

Model Based ΔΔQTcP Estimate (msec)

LS Mean Difference (90% CI)

Bootstrap-Based ΔΔQTcP Estimate (msec)

LS Mean Difference (90% CI)

 

 

127.40

 

2.39 (0.70 to 4.07)

 

2.42 (-0.00 to 4.90)

 

 

213.58

 

4.00 (1.18 to 6.83)

 

4.02 (-0.00 to 8.05)

 

 

2141.10

 

13.73 (12.08 to 15.38)

 

13.76 (11.50 to 16.06)

 

 

4012.67

 

25.74 (22.64 to 28.82)

 

25.79 (21.76 to 29.91)

LS= least square means

Mirtazapine Additional Analyses:

Model-Based Slope Estimate of QTcP vs Concentration (ng * msec/mL): mean 0.019 (95% CI 0.006 to 0.032; p= 0.02

Bootstrap-Based Slope Estimate of QTcP vs Concentration (ng * msec/mL): mean 0.019 (95% CI -0.000 to 0.038)

Mean QTcP change from baseline and mean concentration peak around 2 hours on days 10 and 20; no delayed effect was detected. The upper 90% CI for the ΔΔQTcP (mirtazapine-placebo) at 45 mg dose was <10 ms, which supports the hypothesis that 45 mg of mirtazapine does not affect the QTcP interval to an extent that is clinically meaningful. The 75 mg dose also did not prolong QTc to a clinically significant degree (upper 90% CI for ΔΔQTcP <10 ms). 

Moxifloxacin analysis confirmed that the assay method is adequately sensitive. 

Adverse Events

A total of 50 patients (27%) reported adverse events, most commonly somnolence, nausea, postural dizziness, and headache. Most events were mild to moderate in intensity; no serious events were reported. 

Study Author Conclusions

The trial showed a positive relationship between mirtazapine concentrations and prolongation of the QTc interval. However, the degree of QT prolongation observed with both 45 mg and 75 mg doses of mirtazapine was not at a level generally considered to be clinically meaningful. 

InpharmD Researcher Critique

This study used a robust analysis method to correlate concentration with effect on QTc; however, it is limited by the small sample size and exclusion of patients with significant comorbidities that may be common in patients on mirtazapine, potentially affecting the incidence of QTc prolongation.



References:

Gurkan S, Liu F, Chain A, Gutstein DE. A Study to Assess the Proarrhythmic Potential of Mirtazapine Using Concentration-QTc (C-QTc) Analysis. Clin Pharmacol Drug Dev. 2019;8(4):449-458. doi:10.1002/cpdd.605