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Analysis of Electrocardiographic Data Following Use of Paroxetine in Pediatric Depression and Obsessive-Compulsive Disorder
Analysis of Electrocardiographic Data Following Use of Paroxetine in Pediatric Depression and Obsessive-Compulsive Disorder STAN KRULEWICZ, M.A., DAVID J. CARPENTER, M.S., PHARM.D., REGAN FONG, PH.D., JOSEPH P. HORRIGAN, M.D., ALAN LIPSCHITZ, M.D., PHILIP PERERA, M.D., M.B.A., AND KAREN DINEEN WAGNER, M.D., PH.D.
ABSTRACT Objective: This retrospective analysis of electrocardiographic (ECG) data investigated the cardiovascular effects of paroxetine 10Y50 mg/day in pediatric patients (7Y18 years of age). Data were collected from three 8- to 10-week, randomized, placebo-controlled, double-blind trials of paroxetine in pediatric patients with major depressive disorder or obsessive-compulsive disorder. Method: Electrocardiograms (ECGs) were retrospectively retrieved from 63 study sites in the United States and Canada. Only patients with at least one screening and one on-treatment ECG were included. ECGs were analyzed for heart rate, QT interval corrected using Bazett’s formula (QTcB) and Fridericia’s formula (QTcF), at screening and while being treated. PR, R-R, and QRS intervals and the maximum change in QTcB and QTcF from screening to endpoint were determined. Clinically significant thresholds were defined a priori. Results: A total of 1,451 ECGs from 449 patients receiving placebo (n = 207), paroxetine (n = 200), or imipramine (n = 42) were analyzed. Treatment with paroxetine did not significantly increase QTcB or QTcF or any ECG parameters compared with placebo. Treatment with imipramine significantly increased heart rate and QTcB, R-R, and QRS intervals compared with either paroxetine or placebo. Conclusions: Data from this retrospective study indicate that paroxetine (10Y50 mg/day) is unlikely to be associated with significant ECG changes in medically healthy pediatric patients. J. Am. Acad. Child Adolesc. Psychiatry, 2006;45(4):422Y430. Key Words: paroxetine, pediatric, electrocardiogram, major depressive disorder, obsessive-compulsive disorder.
The selective serotonin reuptake inhibitors (SSRIs) are efficacious and well tolerated in the treatment of Accepted November 1, 2005. This study was funded by GlaxoSmithKline. Mr. Krulewicz, Drs. Carpenter, Fong, and Lipschitz are with GlaxoSmithKline Pharmaceuticals, King of Prussia, PA; Dr. Perera is a former employee of GlaxoSmithKline; Dr. Horrigan is with GlaxoSmithKline Pharmaceuticals, Research Triangle Park, NC; Dr. Wagner is with the Division of Child and Adolescent Psychiatry, University of Texas Medical Branch, Galveston, TX. Correspondence to Stan Krulewicz, Neurosciences Medicines Development Center, GlaxoSmithKline Pharmaceuticals, 2301 Renaissance Boulevard, Building 510, P.O. Box 61540, King of Prussia, PA 19406-2772; e-mail: [email protected]. The authors are grateful to Timothy Callahan, Ph.D., and Angela M. Sharkey, M.D., from Biomedical Systems for their help with the statistical analysis and clinical interpretation of the data, respectively. The authors thank Paul A. McSorley for his advice and assistance and Complete Medical Communications Ltd., Cheshire, U.K., for their help. 0890-8567/06/4504Y0422Ó2006 by the American Academy of Child and Adolescent Psychiatry. DOI: 10.1097/01.chi.0000198593.30702.48
adult psychiatric disorders and have largely replaced tricyclic antidepressants (TCAs) as the treatment of choice for a number of psychiatric disorders in adults including major depressive disorder (MDD), obsessivecompulsive disorder (OCD), and panic disorder (Byram Karasu et al., 2000; Gorman et al., 1998; Vaswani et al., 2003). The cardiovascular effects of the TCAs have caused particular concern, including their effects on orthostatic hypotension, atrioventricular conduction delay, reduced heart rate variability, tachycardia, syncope, and lengthening of the QT interval (Coupland et al., 1997; Giardina et al., 1979; Gutgesell et al., 1999). In contrast, SSRIs have been shown to possess a relatively benign cardiovascular profile in adults (Al-Khatib et al., 2003; Gutgesell et al., 1999; Ray et al., 2004). Two placebocontrolled preliminary studies found that paroxetine had no clinically relevant cardiac effects when given in
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PAROXETINE EFFECTS ON PEDIATRIC ECG
therapeutic doses to adult patients with depression (Edwards et al., 1989; Kuhs and Rudolf, 1990). The SSRIs fluoxetine (Harris and Benfield, 1995), sertraline, and citalopram are also thought to produce no clinically significant cardiovascular events (Goodnick et al., 2002). There are, however, a few case reports that note an association of citalopram with corrected QT (QTc) interval prolongation in adults (Catalano et al., 2001; Meuleman et al., 2001) and two case reports that describe QTc prolongation in patients receiving paroxetine (Erfurth et al., 1998). Although QTc prolongation with citalopram and paroxetine is limited to case reports, there is as yet no definite evidence that SSRIs do not alter the QTc interval. Despite the fact that SSRIs may not directly alter the QTc interval, they can inhibit isoenzymes of cytochrome P-450 that metabolize other drugs that may prolong the QTc interval (Wagstaff et al., 2002). For example, SSRIs, including paroxetine, are known to inhibit cytochrome P-450 2D6 to varying degrees (Lam et al., 2002; Liston et al., 2002). This isoenzyme is known to be involved in the metabolism of a variety of drugs including $-blockers, antidepressants, and antipsychotic agents. Adverse effects can occur when inhibition of the P-450 system leads to elevated levels of coprescribed medications that are capable of prolonging the QT interval and producing multiform ventricular tachycardia (torsade de pointes). SSRIs have emerged as first-line pharmacotherapeutic agents in juvenile psychiatric disorders including MDD, OCD, and anxiety disorders (Emslie et al., 2002; Geller et al., 2004; Reinblatt and Walkup, 2005; Safer et al., 2003; Research Unit on Pediatric Psychopharmacology Anxiety Study Group, 2001). However, few recent studies have reported on the effects of SSRIs on ECG parameters specifically in pediatric patients. In a 12-week placebo-controlled, paralleldesign, multicenter study of sertraline for OCD in 107 children and 80 adolescents, there were no clinically significant cardiovascular adverse events in any of the subjects (Wilens et al., 1999). Moreover, compared with baseline and placebo, sertraline treatment at an average dose of 167 mg/day did not result in any clinically meaningful changes in any ECG indices (PR, QRS, and QTc intervals), cardiac rhythm, blood pressure, or heart rate. A review by the American Heart Association concluded that in pediatric patients
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SSRIs have minimal cardiovascular effects and that even with massive overdose, deaths have been rare (Gutgesell et al., 1999). The purpose of this analysis was to evaluate potential cardiovascular effects of paroxetine in a large group of children and adolescents using a retrospective blinded analysis of ECG data collected originally as part of the safety assessments of three pediatric clinical trials of paroxetine in MDD and OCD. METHOD Subjects ECGs were obtained in three randomized, multicenter, doubleblind, placebo-controlled, flexible-dose trials conducted at 63 sites in the United States and Canada using paroxetine (10Y50 mg/day) in children and adolescents with MDD or OCD (Table 1; Emslie et al., in press ; Geller et al., 2004; Keller et al., 2001). Patients with any clinically significant screening or baseline ECG findings were excluded from these studies. All of the patients provided informed consent/assent; the studies were performed in accordance with Good Clinical Practice and the Declaration of Helsinki and approved by local Institutional Review Boards or Ethics Committees before each center’s initiation. Treatment In study 1 (MDD trial; Keller et al., 2001), patients were titrated to receive 20 mg/day paroxetine or 200 mg/day imipramine during weeks 1 to 4, which could be increased in nonresponders to 40 mg/day paroxetine or 300 mg/day imipramine from weeks 4 to 8. In study 2 (MDD trial; Emslie et al., in press) and study 3 (OCD trial; Geller et al., 2004), patients were initiated on 10 mg/day paroxetine; thereafter, based on clinical response and tolerability, the dose could be gradually increased each week by 10 mg/day to a maximum daily dose of 50 mg paroxetine. Outcome Measures The primary endpoint of interest in this analysis was the QTc interval. Prolongation of the QT/QTc interval is currently the best biomarker for torsade de pointes. To make statements regarding the effect of pharmaceutical compounds on the QT interval, it is necessary to be able to compare the QT interval across heart rates. Because of the variability and correlation with heart rate of the QT interval, techniques to adjust or ‘‘correct’’ the QT interval are necessary. In this study, the R-R interval (R-R: the time between successive electrocardiographic waveforms, which is correlated with heart rate) was corrected using both Bazett’s (QTcB = QT/R-R1/2) and Fridericia’s (QTcF = QT/R-R1/3) formulas. ECG Recordings For all three studies, ECGs were recorded at screening, baseline (if clinically significant abnormal values were noted at the screening visit), and at the end of the double-blind treatment phase (or upon early withdrawal). In addition, ECGs were recorded in study 1 at weeks 2, 4, 6, and 8 (double-blind treatment phase), weeks 13 and 16 (continuation phase), and at the patients’ last visit.
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TABLE 1 Summary of Study Design for the Three North American (US/Canada) Trials Study 1 Study 2 (GSK Study 329) (GSK Study 701) Duration of study Study design (paroxetine vs. control)a Scheduled study visit, wk Screening period, wk Dosing duration, wk Paroxetine dose, mg/day No. of patients in study No. of patients randomized to paroxetine (%) Patient age range, yr Primary diagnosis (DSM-III-R/DSM-IV)
Study 3 (GSK Study 704)
April 1994YMay 1997 March 2000YJanuary 2001 January 2000YJuly 2001 Paroxetine vs. placebo/imipramine Paroxetine vs. placebo Paroxetine vs. placebo vs. placebo 1, 2, 3, 4, 5, 6, 7, 8 1, 2, 3, 4, 6, 8 1, 2, 3, 4, 6, 8, 10 1 1 1 8 10 8b 20Y40 10Y50 10Y50 275 203 203 93 (34) 101 (50) 98 (48) 12Y18 7Y17 7Y17 MDD MDD OCD
Note: GSK = GlaxoSmithKline; MDD = major depressive disorder; OCD = obsessive-compulsive disorder. a Randomization ratio 1:1:1 for study 1 and 1:1 for studies 2 and 3. b Study 1 also included a continuation phase in which responders at week 8 had the option to receive blinded study medication for an additional 6 months.
During the individual studies, 12-lead ECGs were recorded on paper at each investigative site. For the current investigation, a centralized cardiology facility (Biomedical Systems, St. Louis) collected these ECGs retrospectively from the original investigators/study sites. The paper ECGs were digitized, calibrated according to voltage and paper speed, and displayed on a computer screen. The values of the QT, PR, and R-R intervals and QRS duration were measured using computer software using on-screen calipers (Computer-Assisted Measurement of ECG Intervals [CAMI] System, Biomedical Systems). With the CAMI system, the paper ECG is scanned into the computer and displayed on a screen. Four contiguous ECG complexes are identified for measurement. After the system is calibrated, measurements are made from the last three of the four ECG complexes (the first R-R interval is used as a reference for the second QT interval). These measurements are made by the technician placing the original fiducial points. The computer calculates the measurements based on the placement of the fiducial points. The ECGs were analyzed by a single board-certified pediatric cardiologist who was blinded to which study visit the ECG was obtained during, treatment group, and patient identity. The cardiologist performed a diagnostic evaluation of the ECG recordings and identified any clinically abnormal ECGs. In addition, the occurrence of any ECG adverse events during the clinical trials was examined.
maximum observed differences between screening and on-treatment QTc values for all patients were calculated for each treatment group (paroxetine, imipramine, and placebo) and compared using analysis of variance (ANOVA). Whenever appropriate, within-group comparisons were made using paired t tests. Statistical comparisons were made for children and adolescent groups combined, except at screening where statistical analyses for children and adolescent groups were made. When multiple ECGs were taken for a given patient while on-treatment, these ECGs were averaged for the ontreatment analysis. In patients for whom there was a screening and at least one on-treatment ECG, the maximum QTc change from screening was also calculated. Clinically noteworthy QTc interval signals were defined in terms of absolute QTc intervals or changes from screening according to draft recommendations from the U.S. Food and Drug Administration (2003): absolute QTc measurements 9440, 9450, 9480, and 9500 milliseconds; QTc change from screening of 30Y60 and 960 milliseconds. Analyses of QTc interval data between treatment groups were based on the number and percentage of patients meeting or exceeding these predefined threshold values. Differences between treatments were analyzed using either a x2 test or Fisher exact test (when expected frequency of individuals in a group was G5) and an a level of .05 was considered statistically significant. A similar analytical approach was used for the other cardiac conduction intervals including heart rate. No adjustments for multiple comparisons were made.
Statistical Analysis
RESULTS
Data Acquisition
ECGs from all three studies were analyzed separately and combined. The lack of difference between placebo and paroxetine observed in the combined data was consistent with the results seen in each of the three individual studies; therefore, only the combined data are presented. QTc interval data were assessed as central tendency and categorical analyses. The mean QTc interval and mean of the
A total of 449 patients who had at least one screening and at least one on-treatment ECG provided 1,451 evaluable ECGs for analysis. In total, 281 of 449 (62.6%) were diagnosed with MDD (study 1: n = 120
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Patient Population
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PAROXETINE EFFECTS ON PEDIATRIC ECG
Variable
a
QT interval, ms Males/females Children/adolescents QTcB interval, ms Males/females Children/adolescents QTcF interval, ms Males/females Children/adolescents Heart rate, bpm Males/females Children/adolescents R-R interval, ms Males/females Children/adolescents PR interval, ms Males/females Children/adolescents QRS duration, ms Males/females Children/adolescents
TABLE 2 Mean Electrocardiographic Data at Screening Placebo (n = 207) (Mean T SD) Paroxetine (n = 200) (Mean T SD) 353.2 T 28.5 351.3 T 26.1/355.7 T 31.1 341.9 T 26.7/361.2 T 27.1 394.1 T 26.8 388.3 T 26.0/401.4 T 26.2c 395.3 T 22.2/393.2 T 29.7 379.7 T 21.8 375.4 T 20.8/385.2 T 21.9d 376.5 T 17.3/382.0 T 24.2 76.3 T 15.0 74.7 T 13.9/78.3 T 16.2 82.0 T 15.2/72.3 T 13.6 815.7 T 154.3 829.5 T 148.5/798.0 T 160.5 758.2 T 150.2/855.7 T 144.7g 137.5 T 24.3 137.6 T 28.0/137.5 T 18.7 132.8 T 20.5/140.8 T 26.1g 76.4 T 10.3 77.2 T 10.7/75.5 T 9.7 75.3 T 11.3/77.2 T 9.4
353.7 T 31.2 353.5 T 31.9/353.8 T 30.6 343.2 T 28.9/361.5 T 30.6 395.7 T 24.6 390.1 T 26.2/401.5 T 21.6c 397.1 T 25.4/394.7 T 24.2 380.9 T 21.9 377.3 T 24.2/384.6 T 18.7d 378.1 T 22.5/383.1 T 21.3 76.8 T 14.7 74.5 T 13.2/79.1 T 15.8 81.9 T 14.8/73.0 T 13.5 808.1 T 146.5 829.4 T 143.9/786.3 T 146.6d 753.9 T 120.0/849.0 T 151.7g 137.6 T 19.1 139.8 T 20.9/135.4 T 16.9 132.9 T 17.2/141.3 T 19.7 77.1 T 11.6 78.3 T 12.5/75.8 T 10.6 73.6 T 10.6/79.7 T 11.7g
Imipramine (n = 42) (Mean T SD) 366.0 T 26.9b 368.1 T 27.3/364.9 T 27.1 NA/366.0 T 26.9 397.9 T 30.1 399.0 T 29.2/397.3 T 31.0 NA/397.9 T 30.1 386.8 T 25.2 388.1 T 24.1e/386.2 T 26.1 NA/386.8 T 25.2 71.8 T 11.1f 71.4 T 12.1/72.1 T 10.8b NA/71.8 T 11.1 855.6 T 138.8 862.2 T 137.1/852.3 T 142.0f NA/855.6 T 138.8 149.4 T 22.5b 143.9 T 19.0/152.1 T 23.9b NA/149.4 T 22.5 77.6 T 10.4 79.7 T 10.5/76.5 T 10.4 NA/77.6 T 10.4
Note: Analysis of variance was used to test for significance between treatment groups. NA = not available. Overall data are presented, except where specified; b p G .05 versus placebo or paroxetine; c p G .001 versus males; d p G .05 versus males; e p G .05 versus placebo; f p G .05 versus paroxetine only; g p G .05 versus children. a
and study 2: n = 161), and 168 of 449 (37.4%) had a primary diagnosis of OCD (study 3). Overall, the mean age of patients was 12.5 T 3.1 years, with 171 of 449 (38.1%) children (7Y11 years) and 278 of 449 (61.9%) adolescents (12Y18 years). The overall proportions of males and females included in the analysis were approximately equal (231 of 449 [51.5%] and 218 of 449 [48.5%], respectively); however, in study 1, the proportion of males was only 39.2%, compared with 53.4% and 58.3% for studies 2 and 3, respectively.
Screening QTc Interval. Overall, the mean QTcB and QTcF interval values at screening were similar across all three treatment groups (Table 2). Mean Change in QTc Interval From Screening to OnTreatment. Treatment with either placebo or paroxetine did not significantly alter mean QTcB or QTcF indices compared with screening values (Table 3). Treatment with imipramine significantly increased the mean QTcB interval (14.5 milliseconds; p = .010) but not the mean QTcF interval (j3.1 milliseconds; p = .467) between screening and while on-treatment.
The mean change between screening and ontreatment QTcB values was higher with imipramine compared with placebo (14.5 milliseconds versus j1.4 milliseconds, respectively; p G .001) or paroxetine (14.5 milliseconds versus j2.3 milliseconds, respectively; p G .001). QTcB values for placebo- and paroxetine-treated patients were similar. The mean within-group change in QTcF from screening to ontreatment did not differ significantly between any of the treatment groups. Maximum Change in QTc Interval Between Screening and While On-Treatment. For both the QTcB and QTcF intervals, the maximum changes from screening for paroxetine- and placebo-treated patients were comparable. In the imipramine group, the maximum QTcB change from screening was greater than on placebo ( p G .001) or paroxetine ( p G .001). Although the maximum change in QTcF was nearly significantly greater in the imipramine group compared with paroxetine (5.92 milliseconds versus j0.86 milliseconds, respectively; p = .060), no difference was observed between paroxetine and placebo (j0.86 milliseconds versus 1.5 milliseconds, respectively; p = .210).
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QTc Interval Measurements
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KRULEWICZ ET AL.
Variablea
TABLE 3 Mean Electrocardiographic Data After Treatment With Placebo, Paroxetine, and Imipramine Placebo (n = 207) Paroxetine (n = 200) Imipramine (n = 42)
On Treatment (Mean T SD) QT interval, ms 353.6 T 25.0 Children/ 343.9 T 22.0/360.3 T 22.8 adolescents QTcB interval, ms 392.7 T 23.2 Children/ 393.9 T 21.7/391.9 T 24.2 adolescents QTcF interval, ms 379.1 T 18.8 Children/ 376.5 T 17.4/380.9 T 19.6 adolescents Heart rate, bpm 75.4 T 12.8 Children/ 79.9 T 12.4/72.2 T 12.2 adolescents R-R interval, ms 820.5 T 138.8 Children/ 769.2 T 119.5/856.2 T 140.5 adolescents PR interval, ms 139.8 T 23.6 Children/ 134.7 T 19.8/143.4 T 25.3 adolescents QRS duration, ms 76.9 T 10.8 Children/ 75.9 T 11.5/77.6 T 10.3 adolescents
Mean Change From Screening
On-Treatment (Mean T SD)
0.3 2.02/j0.84
349.2 T 27.0 340.2 T 25.8/355.9 T 26.1
b 332.7 T 17.5c j4.5 j3.0/j5.6 NA/332.7 T 17.5
j33.2 NA/j33.2
j1.4 j1.4/j1.4
393.4 T 20.9 392.1 T 18.0/394.5 T 22.9
412.4 T 17.0c j2.3 j5.0/j0.3 NA/412.4 T 17.0
14.5e,f NA/14.5
j0.6 0.03/j1.1
377.9 T 18.8 373.9 T 17.0/381.0 T 19.6
j3.0 j4.2/2.1
383.8 T 14.3g NA/383.8 T 14.3
j3.1 NA/j3.1
j0.9 j2.1/j0.1
77.6 T 12.6 81.0 T 12.5/75.0 T 12.2
0.8 j0.9/2.0
93.3 T 10.0c NA/93.3 T 10.0
21.4d,e NA/21.4
4.8 11.0/0.5
Mean Change From Screening
On-Treatment (Mean T SD)
Mean Change From Screening d,e
d,e 794.8 T 126.0 656.3 T 74.2c j13.3 j199.3 757.8 T 112.9/822.8 T 128.6 3.9 /j26.2 NA/656.3 T 74.2 NA/j199.3
2.3f 1.8/2.6
136.5 T 17.9 132.1 T 14.8/139.8 T 19.4
0.5 0.6/0.4
77.1 T 10.8 73.6 T 9.4/79.7 T 11.0
b 156.9 T 20.4c j1.2 j0.8/j1.5 NA/156.9 T 20.4
0.0 0.0/0.0
82.6 T 8.7i NA/82.6 T 8.7
7.6h NA/7.6 5.1d,e NA/5.1
Note: Within-group comparisons between screening and on-treatment measurements were made using paired t tests. Statistical analyses for children and adolescent groups were not made. NA, not available. a Overall data are presented, except where specified; statistical comparisons were made for children/adolescents groups combined; b p G .05 versus placebo only; c p G .001 versus placebo or paroxetine; d p G .001; analysis of variance was used to test for significance between groups on-treatment: between group comparison of on-treatment values; e p G .001 versus placebo or paroxetine; f p e .05; g p G .05 versus paroxetine only; h p G .05 versus placebo or paroxetine; i p G .05 versus placebo or paroxetine; between group comparison of mean change from screening to on-treatment.
Clinically Noteworthy QTc Change From Screening. A similar proportion of patients in the placebo and paroxetine groups had an increased QTcB interval of 960 milliseconds from screening, whereas significantly more patients in the imipramine group experienced this predefined change compared with either paroxetine (p G .003) or placebo (p G .005) groups (Table 4). Similarly, the percentage of patients with a treatmentemergent QTcB prolongation of 30Y60 milliseconds was significantly higher in imipramine-treated patients compared with paroxetine (p G .001) and placebo (p G .001) treatment. In addition, a significantly greater proportion of imipramine-treated patients had a QTcF interval increase of 30Y60 milliseconds compared with
paroxetine-treated patients (p G .027). Although the proportion of patients with an increased QTcB interval 30Y60 milliseconds from screening was higher in the placebo group compared with the paroxetine group (p G .05), the proportion of patients with an increased QTcF interval 30Y60 milliseconds from screening was similar in the paroxetine and placebo groups. Changes in QTcF from screening 960 milliseconds were comparable between the three treatment groups. Clinically Noteworthy Absolute Maximum QTc Values. A significantly greater percentage of patients treated with imipramine experienced an absolute QTcB value of 9440 milliseconds compared with either placebo (p G .001) or paroxetine (p G .003) (Table 4). For all other predefined absolute QTcB and QTcF intervals, there were no differences between treatment
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Potentially Clinically Significant QTc Measurements
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PAROXETINE EFFECTS ON PEDIATRIC ECG
TABLE 4 Noteworthy On-Treatment QTcB and QTcF Interval Signals Defined in Terms of Absolute QTc Intervals or Changes From Baseline Placebo Paroxetine Imipramine (n = 207) (n = 200) (n = 42) Variable No. (%) No. (%) No. (%) Maximum QTcB change from screening, ms 30Y60 960 Maximum QTcF change from screening, ms 30Y60 960 Absolute QTcB interval, ms 9440 9450 9480 9500 Absolute QTcF interval, ms 9440 9450 9480 9500
absolute on-treatment QTcF value 9450 milliseconds (one placebo, one paroxetine). The reviewing cardiologist did not consider these absolute QTcB threshold values to be clinically significant. Other Electrocardiographic Measurements
groups. None of the treatment groups were associated with a QTcB or QTcF value of 9500 milliseconds. Of the 15 patients (4 placebo, 3 paroxetine, and 8 imipramine) who had a potentially clinically significant absolute prolonged QTcB interval (9440 milliseconds), 4 patients (2 placebo, 1 paroxetine, and 1 imipramine) exceeded this threshold at screening and are not considered further here. Of those remaining, 5 (2 placebo, 1 paroxetine, and 2 imipramine) patients had absolute on-treatment QTcB threshold values of 9450 milliseconds. The reviewing cardiologist considered two of these patients to have potentially clinically significant QTcB measurements: one placebo-treated patient (absolute threshold QTcB value of 9450 milliseconds with a 960-millisecond change from screening) and one imipramine-treated patient (absolute threshold QTcB value of 9480 milliseconds with a QTcB change from baseline of 960 milliseconds). Analysis of the QTcF values showed that two adolescent females had an
Heart Rate. Overall, at screening the mean heart rate in the paroxetine group was similar to that in the placebo group but was significantly higher compared with the imipramine group (Table 2; p = .040). At screening, female patients had higher heart rates compared with male patients in the paroxetine group (p = .028). Females in the placebo and paroxetine groups had higher screening heart rates than those in the imipramine group (p = .022 and p = .029, respectively). No difference in heart rate was observed between genders in the placebo and imipramine groups. Children had higher heart rates compared with adolescents at screening in the placebo (p G .001) and paroxetine (p G .001) groups. There was no change in overall mean heart rate between screening and treatment in the paroxetine (0.8 bpm increase from screening) and placebo (0.9 bpm decrease from screening) groups (Table 3). In the imipramine group, however, mean heart rate significantly increased by 21.4 bpm overall compared with screening values (p G .001). This increase was significantly higher compared with the placebo (p G .001) and paroxetine (p G .001) groups. Analysis of the R-R interval at baseline and during treatment reflected and supported the observations for mean heart rate (Tables 2 and 3). PR Interval. Overall, the screening mean PR interval was comparable between placebo and paroxetine groups (Table 2). Patients in the imipramine group had a longer mean PR interval at screening compared with patients in the paroxetine (p G .001) or placebo groups (p G .004). Female patients in the placebo and paroxetine groups had a shorter PR interval compared with females in the screening imipramine group (p = .001 and p G .001, respectively). In the placebo group, children had a shorter mean PR interval compared with adolescents (p = .020). In placebo-treated patients, the mean PR interval significantly increased by 2.3 milliseconds compared with screening (Table 3; p = .028). The mean PR interval increased slightly but not significantly from screening to treatment in the imipramine group (7.6 milliseconds; p = .069). No differences
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24 (11.6)a 3 (1.5)
10 (5.0) 2 (1.0)
16 (38.1)b,c 5 (11.9)d,e
24 (11.6) 3 (1.5)
5 (2.5) 0 (0)
4 (9.5)f 1 (2.4)
4 (1.9) 3 (1.5) 0 (0) 0 (0)
3 (1.5) 2 (1.0) 0 (0) 0 (0)
8 (19.1)d,g 2 (4.8) 1 (2.4) 0 (0)
1 (0.5) 1 (0.5) 0 (0) 0 (0)
2 (1.0) 1 (0.5) 0 (0) 0 (0)
1 (2.4) 0 (0) 0 (0) 0 (0)
p G .05 versus placebo; b p G .0001 versus placebo; c p G .0001 versus paroxetine; d p G .003 versus paroxetine; e p G .005 versus placebo; f p G .027 versus paroxetine; g p G .0006 versus placebo (all determined using analysis of variance between the three treatment groups). a
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KRULEWICZ ET AL.
were seen in the paroxetine group (j1.2 milliseconds; p = .158). Comparison of the difference between ontreatment and screening PR values between treatments showed that imipramine increased the PR interval compared with placebo (p = .028) and paroxetine (p G .001), whereas paroxetine decreased the PR interval compared with placebo (p = .013). QRS Duration. There were no significant differences in the mean QRS duration overall between treatment groups at screening (Table 2). Children had a shorter QRS value compared with adolescents in the screening paroxetine group (p G .001). No changes in the mean QRS duration were observed in either the placebo or paroxetine groups between screening and treatment, but imipramine treatment significantly increased the mean QRS duration by 5.1 milliseconds compared with screening (Table 3; p = .001). The mean change in QRS duration from screening to on-treatment was significantly higher in the imipramine group (5.1-millisecond increase) compared with either placebo (0.5-millisecond increase; p G .001) or paroxetine (0.0 milliseconds; p G .001).
underlying conduction abnormality and further evaluation of this patient by a pediatric cardiologist was recommended. DISCUSSION
In study 1, six patients had treatment-emergent cardiovascular adverse events that led to withdrawal from the study: nodal arrhythmia in one patient on placebo; atrioventricular (AV) block in one patient on paroxetine (investigator assessed causality was possibly related to study medication); and four different imipramine patients with four disparate findings: arrhythmia, abnormal ECG, extrasystoles, and a prolonged QT interval with AV block (investigator assessed causalities were possibly related and related to study medication). No abnormal ECG assessments were observed in study 2, and in study 3, only one patient in the placebo group had an abnormal ECG assessment, as judged by the treating investigator. During the post hoc analysis of these data, it was discovered that one patient in the paroxetine group had an abnormal ECG at screening with evidence consistent with low right atrial rhythm and Wolf-ParkinsonWhite syndrome. These same findings were noted on the ECG performed at the trial end (week 8). Because this was not reported as part of the patient’s initial medical history or as a study adverse event, the principal investigator was notified regarding the possibility of an
This retrospective analysis of ECG interval data from three double-blind, placebo-controlled trials of paroxetine in children and adolescents with MDD or OCD suggested that paroxetine was not associated with prolongation of QTcB or QTcF or other indices of cardiac conduction in this patient population. The majority of patients in the placebo and paroxetine groups experienced no significant changes in ECG intervals between screening and on-treatment measurements. These findings are consistent with results from controlled adult studies, which indicate that paroxetine has no systematic impact on adult cardiac conduction (Boyer and Blumhardt, 1992). This analysis showed that no patient experienced a prolonged QTcB or QTcF value of 9500 milliseconds while on-treatment in any group. Using the clinically noteworthy QTc interval (of 9440 milliseconds), 98.5% of patients receiving paroxetine had a normal QTcB interval compared with 98% in the placebo group and 81% in the imipramine group. Therefore, a prolonged QTc interval only occurred in three outlying patients in the paroxetine and four in the placebo groups, and these cases were not considered to be clinically significant. In the present analysis, imipramine served as a positive control because it is known to significantly increase ECG parameters such as heart rate, QRS duration, and mean change in QTcB between screening and on treatment (Giardina et al., 1979; Gutgesell et al., 1999). As expected, imipramine significantly altered a number of ECG measurements compared with paroxetine or placebo treatment. In the imipramine group, the change in QTcB interval on-treatment was significantly longer compared with screening values, but there was no significant difference in the corresponding mean change in QTcF interval between screening and treatment. The discrepancy between these results may be caused by the increase in heart rate observed in imipramine-treated patients and the slight variation in the way this increase is incorporated into the QTcB and QTcF correction methods. It is also possible that the increase in QTcB interval between screening and imipramine treatment
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Electrocardiographic Adverse Events Reported During the Clinical Trials
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may be associated with the increased QRS duration observed in these patients. The heart rate was unaffected by treatment in the placebo and paroxetine groups; therefore, there was no major discrepancy in results for the QTcB and QTcF intervals within these groups.
Limitations
The retrospective nature of the analysis, particularly with regard to the retrieval of ECG data from study centers from as far back as 1994, is a limitation because ECG data of approximately two thirds of the patients randomized were available for retrieval. Original ECGs were obtained from a number of study sites using different equipment, which may contribute to variability within the data set. Only a single ECG was available at each time point, and none of the ECGs were digitally recorded. Therefore, ECGs had to be digitized before intervals could be annotated and over-read. Six study sites did not return any ECGs for analysis, and data for some patients were excluded if at least one screening and at least one on-treatment ECG were not available or caused by poor overall quality of some ECGs. Some commonly occurring comorbid conditions in children and adolescents with depression or OCD were exclusion criteria for the three studies included in this analysis. In general, no other concomitant pharmacotherapy for psychiatric illness was permissible. Also, patients with clinically significant ECG abnormalities at baseline were to be excluded from these studies. These limitations may therefore affect the ability to generalize the findings to the broader population. Additional studies may be necessary to identify which children may be at increased risk of possible cardiac events. In addition to the studies being short term (8Y10 weeks), no information regarding the relationship between medication dose and/or duration of exposure to medication on ECG tracings was collected in these studies, which further limits the conclusions that can be drawn from these data. Although this represents the largest analysis of cardiovascular functioning in children and adolescents receiving an SSRI to date, statistical comparisons between children and adolescent groups were only made at screening; therefore, any conclusions about age-related treatment differences between these two groups cannot be made. Moreover, despite the large
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sample size, the possibility of rare events cannot be precluded. It should also be noted that the imipramine group only included adolescents, whereas both children and adolescents comprised patients in the placebo and paroxetine groups. It is therefore possible that the observed differences between treatment groups arose because of the varying age of patients; however, the lack of difference observed between paroxetine and placebo appears consistent in children and adolescents.
Clinical Implications
Based on the comparison of cardiac conduction intervals in patients treated with paroxetine and placebo, these results suggest that paroxetine is unlikely to cause clinically significant prolongation of these intervals in pediatric patients. These data were gathered retrospectively from three previously completed clinical trials assessing the efficacy, tolerability, and short-term safety of paroxetine. These observations are consistent with those of previous studies investigating the cardiovascular effects of paroxetine in adult patients with depression (Edwards et al., 1989; Kuhs and Rudolf, 1990). The current analyses support published guidelines concerning ECG monitoring in children and adolescents, namely, that extensive ECG monitoring is not required for patients receiving paroxetine (Francis, 2002; Gutgesell et al., 1999). ECG monitoring is indicated, however, if paroxetine is coprescribed with drugs that cause QTc prolongation or that share the same metabolic pathways or where clinically indicated based on individual and familial history. Findings from this retrospective analysis address the cardiovascular effects of paroxetine in the pediatric population. The use of antidepressants, including paroxetine, in patients younger than 18 years old has been scrutinized by regulatory authorities because of concerns of increased risks of suicidal ideation, suicide attempts, or self-harm. Recently, a U.S. Food and Drug Administration advisory committee concluded that there is an increased risk of suicidality in children and adolescents receiving antidepressants. As a result, the U.S. Food and Drug Administration required antidepressants to carry ‘‘black box’’ warnings about the risk of increased suicidal tendencies and careful monitoring of children receiving SSRIs. Paroxetine is not approved for use in pediatric patients.
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Al-Khatib SM, LaPointe NM, Kramer JM, Califf RM (2003), What clinicians should know about the QT interval. JAMA 289:2120Y2127 Boyer WF, Blumhardt CL (1992), The safety profile of paroxetine. J Clin Psychiatry 53(suppl):61Y66 Byram Karasu T, Gelenberg A, Merriam A, Wang P (2000), Practice Guidelines for the Treatment of Patients With Major Depressive Disorder, 2nd ed., Washington, DC: American Psychiatric Association Catalano G, Catalano MC, Epstein MA, Tsambiras PE (2001), QTc interval prolongation associated with citalopram overdose: a case report and literature review. Clin Neuropharmacol 24:158Y162 Coupland N, Wilson S, Nutt D (1997), Antidepressant drugs and the cardiovascular system: a comparison of tricyclics and selective serotonin reuptake inhibitors and their relevance for the treatment of psychiatric patients with cardiovascular problems. J Psychopharmacol 11:83Y92 Edwards JG, Goldie A, Papayanni-Papasthatis S (1989), Effect of paroxetine on the electrocardiogram. Psychopharmacology (Berl) 97:96Y98 Emslie GJ, Heiligenstein JH, Wagner KD et al. (2002), Fluoxetine for acute treatment of depression in children and adolescents: a placebocontrolled, randomized clinical trial. J Am Acad Child Adolesc Psychiatry 41:1205Y1215 Emslie GJ, Wagner KD, Kutcher S et al. (in press), Paroxetine treatment in children and adolescents with major depressive disorder: a randomized, multicenter, double-blind, placebo-controlled trial. J Am Acad Child Adolesc Psychiatry Erfurth A, Loew M, Dobmeier P, Wendler G (1998), ECG changes after paroxetine. 3 case reports. Nervenarzt 69:629Y631 Francis PD (2002), Effects of psychotropic medications on the pediatric electrocardiogram and recommendations for monitoring. Curr Opin Pediatr 14:224Y230 Geller DA, Wagner KD, Emslie G et al. (2004), Paroxetine treatment in children and adolescents with obsessive-compulsive disorder: a randomized, multicenter, double-blind, placebo-controlled trial. J Am Acad Child Adolesc Psychiatry 43:1387Y1396 Giardina EG, Bigger JT, Jr, Glassman AH, Perel JM, Kantor SJ (1979), The electrocardiographic and antiarrhythmic effects of imipramine hydrochloride at therapeutic plasma concentrations. Circulation 60: 1045Y1052
Goodnick PJ, Jerry J, Parra F (2002), Psychotropic drugs and the ECG: focus on the QTc interval. Expert Opin Pharmacother 3:479Y498 Gorman J, Shear K, Cowley D (1998), Practice Guidelines for the Treatment of Patients With Panic Disorder. Washington, DC: American Psychiatric Association Gutgesell H, Atkins D, Barst R et al.(1999), Cardiovascular monitoring of children and adolescents receiving psychotropic drugs: a statement for healthcare professionals from the Committee on Congenital Cardiac Defects, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation 99:979Y982 Harris MG, Benfield P (1995), Fluoxetine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in older patients with depressive illness. Drugs Aging 6:64Y84 Keller MB, Ryan ND, Strober M et al. (2001), Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. J Am Acad Child Adolesc Psychiatry 40:762Y772 Kuhs H, Rudolf GA (1990), Cardiovascular effects of paroxetine. Psychopharmacology (Berl) 102:379Y382 Lam YW, Gaedigk A, Ereshefsky L, Alfaro CL, Simpson J (2002), CYP2D6 inhibition by selective serotonin reuptake inhibitors: analysis of achievable steady-state plasma concentrations and the effect of ultrarapid metabolism at CYP2D6. Pharmacotherapy 22:1001Y1006 Liston HL, DeVane CL, Boulton DW, Risch SC, Markowitz JS, Goldman J (2002), Differential time course of cytochrome P450 2D6 enzyme inhibition by fluoxetine, sertraline, and paroxetine in healthy volunteers. J Clin Psychopharmacol 22:169Y173 Meuleman C, Jourdain P, Bellorini M et al. (2001), Citalopram and torsades de pointes. A case report. Arch Mal Coeur Vaiss 94:1021Y1024 Ray WA, Meredith S, Thapa PB, Hall K, Murray KT (2004), Cyclic antidepressants and the risk of sudden cardiac death. Clin Pharmacol Ther 75:234Y241 Reinblatt SP, Walkup JT (2005), Psychopharmacologic treatment of pediatric anxiety disorders. Child Adolesc Psychiatr Clin N Am 14:877Y908 Safer DJ, Zito JM, DosReis S (2003), Concomitant psychotropic medication for youths. Am J Psychiatry 160:438Y449 Research Unit on Pediatric Psychopharmacology Anxiety Study Group (2001), Fluvoxamine for the treatment of anxiety disorders in children and adolescents. N Engl J Med 344:1279Y1285 U.S. Food and Drug Administration (2003), E14 clinical evaluation of QT/ QTc interval prolongation and proarrhythmic potential for nonantiarrhythmic drugs; http://www.fda.gov/ohrms/dockets/98fr/2004d0377-gdl0001.doc; accessed November 3, 2005 Vaswani M, Linda FK, Ramesh S (2003), Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review. Prog Neuropsychopharmacol Biol Psychiatry 27:85Y102 Wagstaff AJ, Cheer SM, Matheson AJ, Ormrod D, Goa KL (2002), Paroxetine: an update of its use in psychiatric disorders in adults. Drugs 62:655Y703 Wilens TE, Biederman J, March JS et al. (1999), Absence of cardiovascular adverse effects of sertraline in children and adolescents. J Am Acad Child Adolesc Psychiatry 38:573Y577
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Disclosure: Mr. Krulewicz, Drs. Carpenter, Fong, Horrigan and Lipschitz are employees of GlaxoSmithKline and may own stock in the company. Dr. Perera is a former employee of GlaxoSmithKline and may own company stock. Dr. Wagner receives active research support from Eli Lilly, National Institute of Mental Health, and Organon and is a consultant to Abbott Laboratories, Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Janssen, Jazz Pharmaceuticals, Novartis, Ortho-McNeil, Otsuka, Pfizer, and the National Institute of Mental Health Advisory Council. REFERENCES
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ABSTRACT Objective: This retrospective analysis of electrocardiographic (ECG) data investigated the cardiovascular effects of paroxetine 10Y50 mg/day in pediatric patients (7Y18 years of age). Data were collected from three 8- to 10-week, randomized, placebo-controlled, double-blind trials of paroxetine in pediatric patients with major depressive disorder or obsessive-compulsive disorder. Method: Electrocardiograms (ECGs) were retrospectively retrieved from 63 study sites in the United States and Canada. Only patients with at least one screening and one on-treatment ECG were included. ECGs were analyzed for heart rate, QT interval corrected using Bazett’s formula (QTcB) and Fridericia’s formula (QTcF), at screening and while being treated. PR, R-R, and QRS intervals and the maximum change in QTcB and QTcF from screening to endpoint were determined. Clinically significant thresholds were defined a priori. Results: A total of 1,451 ECGs from 449 patients receiving placebo (n = 207), paroxetine (n = 200), or imipramine (n = 42) were analyzed. Treatment with paroxetine did not significantly increase QTcB or QTcF or any ECG parameters compared with placebo. Treatment with imipramine significantly increased heart rate and QTcB, R-R, and QRS intervals compared with either paroxetine or placebo. Conclusions: Data from this retrospective study indicate that paroxetine (10Y50 mg/day) is unlikely to be associated with significant ECG changes in medically healthy pediatric patients. J. Am. Acad. Child Adolesc. Psychiatry, 2006;45(4):422Y430. Key Words: paroxetine, pediatric, electrocardiogram, major depressive disorder, obsessive-compulsive disorder.
The selective serotonin reuptake inhibitors (SSRIs) are efficacious and well tolerated in the treatment of Accepted November 1, 2005. This study was funded by GlaxoSmithKline. Mr. Krulewicz, Drs. Carpenter, Fong, and Lipschitz are with GlaxoSmithKline Pharmaceuticals, King of Prussia, PA; Dr. Perera is a former employee of GlaxoSmithKline; Dr. Horrigan is with GlaxoSmithKline Pharmaceuticals, Research Triangle Park, NC; Dr. Wagner is with the Division of Child and Adolescent Psychiatry, University of Texas Medical Branch, Galveston, TX. Correspondence to Stan Krulewicz, Neurosciences Medicines Development Center, GlaxoSmithKline Pharmaceuticals, 2301 Renaissance Boulevard, Building 510, P.O. Box 61540, King of Prussia, PA 19406-2772; e-mail: [email protected]. The authors are grateful to Timothy Callahan, Ph.D., and Angela M. Sharkey, M.D., from Biomedical Systems for their help with the statistical analysis and clinical interpretation of the data, respectively. The authors thank Paul A. McSorley for his advice and assistance and Complete Medical Communications Ltd., Cheshire, U.K., for their help. 0890-8567/06/4504Y0422Ó2006 by the American Academy of Child and Adolescent Psychiatry. DOI: 10.1097/01.chi.0000198593.30702.48
adult psychiatric disorders and have largely replaced tricyclic antidepressants (TCAs) as the treatment of choice for a number of psychiatric disorders in adults including major depressive disorder (MDD), obsessivecompulsive disorder (OCD), and panic disorder (Byram Karasu et al., 2000; Gorman et al., 1998; Vaswani et al., 2003). The cardiovascular effects of the TCAs have caused particular concern, including their effects on orthostatic hypotension, atrioventricular conduction delay, reduced heart rate variability, tachycardia, syncope, and lengthening of the QT interval (Coupland et al., 1997; Giardina et al., 1979; Gutgesell et al., 1999). In contrast, SSRIs have been shown to possess a relatively benign cardiovascular profile in adults (Al-Khatib et al., 2003; Gutgesell et al., 1999; Ray et al., 2004). Two placebocontrolled preliminary studies found that paroxetine had no clinically relevant cardiac effects when given in
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therapeutic doses to adult patients with depression (Edwards et al., 1989; Kuhs and Rudolf, 1990). The SSRIs fluoxetine (Harris and Benfield, 1995), sertraline, and citalopram are also thought to produce no clinically significant cardiovascular events (Goodnick et al., 2002). There are, however, a few case reports that note an association of citalopram with corrected QT (QTc) interval prolongation in adults (Catalano et al., 2001; Meuleman et al., 2001) and two case reports that describe QTc prolongation in patients receiving paroxetine (Erfurth et al., 1998). Although QTc prolongation with citalopram and paroxetine is limited to case reports, there is as yet no definite evidence that SSRIs do not alter the QTc interval. Despite the fact that SSRIs may not directly alter the QTc interval, they can inhibit isoenzymes of cytochrome P-450 that metabolize other drugs that may prolong the QTc interval (Wagstaff et al., 2002). For example, SSRIs, including paroxetine, are known to inhibit cytochrome P-450 2D6 to varying degrees (Lam et al., 2002; Liston et al., 2002). This isoenzyme is known to be involved in the metabolism of a variety of drugs including $-blockers, antidepressants, and antipsychotic agents. Adverse effects can occur when inhibition of the P-450 system leads to elevated levels of coprescribed medications that are capable of prolonging the QT interval and producing multiform ventricular tachycardia (torsade de pointes). SSRIs have emerged as first-line pharmacotherapeutic agents in juvenile psychiatric disorders including MDD, OCD, and anxiety disorders (Emslie et al., 2002; Geller et al., 2004; Reinblatt and Walkup, 2005; Safer et al., 2003; Research Unit on Pediatric Psychopharmacology Anxiety Study Group, 2001). However, few recent studies have reported on the effects of SSRIs on ECG parameters specifically in pediatric patients. In a 12-week placebo-controlled, paralleldesign, multicenter study of sertraline for OCD in 107 children and 80 adolescents, there were no clinically significant cardiovascular adverse events in any of the subjects (Wilens et al., 1999). Moreover, compared with baseline and placebo, sertraline treatment at an average dose of 167 mg/day did not result in any clinically meaningful changes in any ECG indices (PR, QRS, and QTc intervals), cardiac rhythm, blood pressure, or heart rate. A review by the American Heart Association concluded that in pediatric patients
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SSRIs have minimal cardiovascular effects and that even with massive overdose, deaths have been rare (Gutgesell et al., 1999). The purpose of this analysis was to evaluate potential cardiovascular effects of paroxetine in a large group of children and adolescents using a retrospective blinded analysis of ECG data collected originally as part of the safety assessments of three pediatric clinical trials of paroxetine in MDD and OCD. METHOD Subjects ECGs were obtained in three randomized, multicenter, doubleblind, placebo-controlled, flexible-dose trials conducted at 63 sites in the United States and Canada using paroxetine (10Y50 mg/day) in children and adolescents with MDD or OCD (Table 1; Emslie et al., in press ; Geller et al., 2004; Keller et al., 2001). Patients with any clinically significant screening or baseline ECG findings were excluded from these studies. All of the patients provided informed consent/assent; the studies were performed in accordance with Good Clinical Practice and the Declaration of Helsinki and approved by local Institutional Review Boards or Ethics Committees before each center’s initiation. Treatment In study 1 (MDD trial; Keller et al., 2001), patients were titrated to receive 20 mg/day paroxetine or 200 mg/day imipramine during weeks 1 to 4, which could be increased in nonresponders to 40 mg/day paroxetine or 300 mg/day imipramine from weeks 4 to 8. In study 2 (MDD trial; Emslie et al., in press) and study 3 (OCD trial; Geller et al., 2004), patients were initiated on 10 mg/day paroxetine; thereafter, based on clinical response and tolerability, the dose could be gradually increased each week by 10 mg/day to a maximum daily dose of 50 mg paroxetine. Outcome Measures The primary endpoint of interest in this analysis was the QTc interval. Prolongation of the QT/QTc interval is currently the best biomarker for torsade de pointes. To make statements regarding the effect of pharmaceutical compounds on the QT interval, it is necessary to be able to compare the QT interval across heart rates. Because of the variability and correlation with heart rate of the QT interval, techniques to adjust or ‘‘correct’’ the QT interval are necessary. In this study, the R-R interval (R-R: the time between successive electrocardiographic waveforms, which is correlated with heart rate) was corrected using both Bazett’s (QTcB = QT/R-R1/2) and Fridericia’s (QTcF = QT/R-R1/3) formulas. ECG Recordings For all three studies, ECGs were recorded at screening, baseline (if clinically significant abnormal values were noted at the screening visit), and at the end of the double-blind treatment phase (or upon early withdrawal). In addition, ECGs were recorded in study 1 at weeks 2, 4, 6, and 8 (double-blind treatment phase), weeks 13 and 16 (continuation phase), and at the patients’ last visit.
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TABLE 1 Summary of Study Design for the Three North American (US/Canada) Trials Study 1 Study 2 (GSK Study 329) (GSK Study 701) Duration of study Study design (paroxetine vs. control)a Scheduled study visit, wk Screening period, wk Dosing duration, wk Paroxetine dose, mg/day No. of patients in study No. of patients randomized to paroxetine (%) Patient age range, yr Primary diagnosis (DSM-III-R/DSM-IV)
Study 3 (GSK Study 704)
April 1994YMay 1997 March 2000YJanuary 2001 January 2000YJuly 2001 Paroxetine vs. placebo/imipramine Paroxetine vs. placebo Paroxetine vs. placebo vs. placebo 1, 2, 3, 4, 5, 6, 7, 8 1, 2, 3, 4, 6, 8 1, 2, 3, 4, 6, 8, 10 1 1 1 8 10 8b 20Y40 10Y50 10Y50 275 203 203 93 (34) 101 (50) 98 (48) 12Y18 7Y17 7Y17 MDD MDD OCD
Note: GSK = GlaxoSmithKline; MDD = major depressive disorder; OCD = obsessive-compulsive disorder. a Randomization ratio 1:1:1 for study 1 and 1:1 for studies 2 and 3. b Study 1 also included a continuation phase in which responders at week 8 had the option to receive blinded study medication for an additional 6 months.
During the individual studies, 12-lead ECGs were recorded on paper at each investigative site. For the current investigation, a centralized cardiology facility (Biomedical Systems, St. Louis) collected these ECGs retrospectively from the original investigators/study sites. The paper ECGs were digitized, calibrated according to voltage and paper speed, and displayed on a computer screen. The values of the QT, PR, and R-R intervals and QRS duration were measured using computer software using on-screen calipers (Computer-Assisted Measurement of ECG Intervals [CAMI] System, Biomedical Systems). With the CAMI system, the paper ECG is scanned into the computer and displayed on a screen. Four contiguous ECG complexes are identified for measurement. After the system is calibrated, measurements are made from the last three of the four ECG complexes (the first R-R interval is used as a reference for the second QT interval). These measurements are made by the technician placing the original fiducial points. The computer calculates the measurements based on the placement of the fiducial points. The ECGs were analyzed by a single board-certified pediatric cardiologist who was blinded to which study visit the ECG was obtained during, treatment group, and patient identity. The cardiologist performed a diagnostic evaluation of the ECG recordings and identified any clinically abnormal ECGs. In addition, the occurrence of any ECG adverse events during the clinical trials was examined.
maximum observed differences between screening and on-treatment QTc values for all patients were calculated for each treatment group (paroxetine, imipramine, and placebo) and compared using analysis of variance (ANOVA). Whenever appropriate, within-group comparisons were made using paired t tests. Statistical comparisons were made for children and adolescent groups combined, except at screening where statistical analyses for children and adolescent groups were made. When multiple ECGs were taken for a given patient while on-treatment, these ECGs were averaged for the ontreatment analysis. In patients for whom there was a screening and at least one on-treatment ECG, the maximum QTc change from screening was also calculated. Clinically noteworthy QTc interval signals were defined in terms of absolute QTc intervals or changes from screening according to draft recommendations from the U.S. Food and Drug Administration (2003): absolute QTc measurements 9440, 9450, 9480, and 9500 milliseconds; QTc change from screening of 30Y60 and 960 milliseconds. Analyses of QTc interval data between treatment groups were based on the number and percentage of patients meeting or exceeding these predefined threshold values. Differences between treatments were analyzed using either a x2 test or Fisher exact test (when expected frequency of individuals in a group was G5) and an a level of .05 was considered statistically significant. A similar analytical approach was used for the other cardiac conduction intervals including heart rate. No adjustments for multiple comparisons were made.
Statistical Analysis
RESULTS
Data Acquisition
ECGs from all three studies were analyzed separately and combined. The lack of difference between placebo and paroxetine observed in the combined data was consistent with the results seen in each of the three individual studies; therefore, only the combined data are presented. QTc interval data were assessed as central tendency and categorical analyses. The mean QTc interval and mean of the
A total of 449 patients who had at least one screening and at least one on-treatment ECG provided 1,451 evaluable ECGs for analysis. In total, 281 of 449 (62.6%) were diagnosed with MDD (study 1: n = 120
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Patient Population
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Variable
a
QT interval, ms Males/females Children/adolescents QTcB interval, ms Males/females Children/adolescents QTcF interval, ms Males/females Children/adolescents Heart rate, bpm Males/females Children/adolescents R-R interval, ms Males/females Children/adolescents PR interval, ms Males/females Children/adolescents QRS duration, ms Males/females Children/adolescents
TABLE 2 Mean Electrocardiographic Data at Screening Placebo (n = 207) (Mean T SD) Paroxetine (n = 200) (Mean T SD) 353.2 T 28.5 351.3 T 26.1/355.7 T 31.1 341.9 T 26.7/361.2 T 27.1 394.1 T 26.8 388.3 T 26.0/401.4 T 26.2c 395.3 T 22.2/393.2 T 29.7 379.7 T 21.8 375.4 T 20.8/385.2 T 21.9d 376.5 T 17.3/382.0 T 24.2 76.3 T 15.0 74.7 T 13.9/78.3 T 16.2 82.0 T 15.2/72.3 T 13.6 815.7 T 154.3 829.5 T 148.5/798.0 T 160.5 758.2 T 150.2/855.7 T 144.7g 137.5 T 24.3 137.6 T 28.0/137.5 T 18.7 132.8 T 20.5/140.8 T 26.1g 76.4 T 10.3 77.2 T 10.7/75.5 T 9.7 75.3 T 11.3/77.2 T 9.4
353.7 T 31.2 353.5 T 31.9/353.8 T 30.6 343.2 T 28.9/361.5 T 30.6 395.7 T 24.6 390.1 T 26.2/401.5 T 21.6c 397.1 T 25.4/394.7 T 24.2 380.9 T 21.9 377.3 T 24.2/384.6 T 18.7d 378.1 T 22.5/383.1 T 21.3 76.8 T 14.7 74.5 T 13.2/79.1 T 15.8 81.9 T 14.8/73.0 T 13.5 808.1 T 146.5 829.4 T 143.9/786.3 T 146.6d 753.9 T 120.0/849.0 T 151.7g 137.6 T 19.1 139.8 T 20.9/135.4 T 16.9 132.9 T 17.2/141.3 T 19.7 77.1 T 11.6 78.3 T 12.5/75.8 T 10.6 73.6 T 10.6/79.7 T 11.7g
Imipramine (n = 42) (Mean T SD) 366.0 T 26.9b 368.1 T 27.3/364.9 T 27.1 NA/366.0 T 26.9 397.9 T 30.1 399.0 T 29.2/397.3 T 31.0 NA/397.9 T 30.1 386.8 T 25.2 388.1 T 24.1e/386.2 T 26.1 NA/386.8 T 25.2 71.8 T 11.1f 71.4 T 12.1/72.1 T 10.8b NA/71.8 T 11.1 855.6 T 138.8 862.2 T 137.1/852.3 T 142.0f NA/855.6 T 138.8 149.4 T 22.5b 143.9 T 19.0/152.1 T 23.9b NA/149.4 T 22.5 77.6 T 10.4 79.7 T 10.5/76.5 T 10.4 NA/77.6 T 10.4
Note: Analysis of variance was used to test for significance between treatment groups. NA = not available. Overall data are presented, except where specified; b p G .05 versus placebo or paroxetine; c p G .001 versus males; d p G .05 versus males; e p G .05 versus placebo; f p G .05 versus paroxetine only; g p G .05 versus children. a
and study 2: n = 161), and 168 of 449 (37.4%) had a primary diagnosis of OCD (study 3). Overall, the mean age of patients was 12.5 T 3.1 years, with 171 of 449 (38.1%) children (7Y11 years) and 278 of 449 (61.9%) adolescents (12Y18 years). The overall proportions of males and females included in the analysis were approximately equal (231 of 449 [51.5%] and 218 of 449 [48.5%], respectively); however, in study 1, the proportion of males was only 39.2%, compared with 53.4% and 58.3% for studies 2 and 3, respectively.
Screening QTc Interval. Overall, the mean QTcB and QTcF interval values at screening were similar across all three treatment groups (Table 2). Mean Change in QTc Interval From Screening to OnTreatment. Treatment with either placebo or paroxetine did not significantly alter mean QTcB or QTcF indices compared with screening values (Table 3). Treatment with imipramine significantly increased the mean QTcB interval (14.5 milliseconds; p = .010) but not the mean QTcF interval (j3.1 milliseconds; p = .467) between screening and while on-treatment.
The mean change between screening and ontreatment QTcB values was higher with imipramine compared with placebo (14.5 milliseconds versus j1.4 milliseconds, respectively; p G .001) or paroxetine (14.5 milliseconds versus j2.3 milliseconds, respectively; p G .001). QTcB values for placebo- and paroxetine-treated patients were similar. The mean within-group change in QTcF from screening to ontreatment did not differ significantly between any of the treatment groups. Maximum Change in QTc Interval Between Screening and While On-Treatment. For both the QTcB and QTcF intervals, the maximum changes from screening for paroxetine- and placebo-treated patients were comparable. In the imipramine group, the maximum QTcB change from screening was greater than on placebo ( p G .001) or paroxetine ( p G .001). Although the maximum change in QTcF was nearly significantly greater in the imipramine group compared with paroxetine (5.92 milliseconds versus j0.86 milliseconds, respectively; p = .060), no difference was observed between paroxetine and placebo (j0.86 milliseconds versus 1.5 milliseconds, respectively; p = .210).
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QTc Interval Measurements
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KRULEWICZ ET AL.
Variablea
TABLE 3 Mean Electrocardiographic Data After Treatment With Placebo, Paroxetine, and Imipramine Placebo (n = 207) Paroxetine (n = 200) Imipramine (n = 42)
On Treatment (Mean T SD) QT interval, ms 353.6 T 25.0 Children/ 343.9 T 22.0/360.3 T 22.8 adolescents QTcB interval, ms 392.7 T 23.2 Children/ 393.9 T 21.7/391.9 T 24.2 adolescents QTcF interval, ms 379.1 T 18.8 Children/ 376.5 T 17.4/380.9 T 19.6 adolescents Heart rate, bpm 75.4 T 12.8 Children/ 79.9 T 12.4/72.2 T 12.2 adolescents R-R interval, ms 820.5 T 138.8 Children/ 769.2 T 119.5/856.2 T 140.5 adolescents PR interval, ms 139.8 T 23.6 Children/ 134.7 T 19.8/143.4 T 25.3 adolescents QRS duration, ms 76.9 T 10.8 Children/ 75.9 T 11.5/77.6 T 10.3 adolescents
Mean Change From Screening
On-Treatment (Mean T SD)
0.3 2.02/j0.84
349.2 T 27.0 340.2 T 25.8/355.9 T 26.1
b 332.7 T 17.5c j4.5 j3.0/j5.6 NA/332.7 T 17.5
j33.2 NA/j33.2
j1.4 j1.4/j1.4
393.4 T 20.9 392.1 T 18.0/394.5 T 22.9
412.4 T 17.0c j2.3 j5.0/j0.3 NA/412.4 T 17.0
14.5e,f NA/14.5
j0.6 0.03/j1.1
377.9 T 18.8 373.9 T 17.0/381.0 T 19.6
j3.0 j4.2/2.1
383.8 T 14.3g NA/383.8 T 14.3
j3.1 NA/j3.1
j0.9 j2.1/j0.1
77.6 T 12.6 81.0 T 12.5/75.0 T 12.2
0.8 j0.9/2.0
93.3 T 10.0c NA/93.3 T 10.0
21.4d,e NA/21.4
4.8 11.0/0.5
Mean Change From Screening
On-Treatment (Mean T SD)
Mean Change From Screening d,e
d,e 794.8 T 126.0 656.3 T 74.2c j13.3 j199.3 757.8 T 112.9/822.8 T 128.6 3.9 /j26.2 NA/656.3 T 74.2 NA/j199.3
2.3f 1.8/2.6
136.5 T 17.9 132.1 T 14.8/139.8 T 19.4
0.5 0.6/0.4
77.1 T 10.8 73.6 T 9.4/79.7 T 11.0
b 156.9 T 20.4c j1.2 j0.8/j1.5 NA/156.9 T 20.4
0.0 0.0/0.0
82.6 T 8.7i NA/82.6 T 8.7
7.6h NA/7.6 5.1d,e NA/5.1
Note: Within-group comparisons between screening and on-treatment measurements were made using paired t tests. Statistical analyses for children and adolescent groups were not made. NA, not available. a Overall data are presented, except where specified; statistical comparisons were made for children/adolescents groups combined; b p G .05 versus placebo only; c p G .001 versus placebo or paroxetine; d p G .001; analysis of variance was used to test for significance between groups on-treatment: between group comparison of on-treatment values; e p G .001 versus placebo or paroxetine; f p e .05; g p G .05 versus paroxetine only; h p G .05 versus placebo or paroxetine; i p G .05 versus placebo or paroxetine; between group comparison of mean change from screening to on-treatment.
Clinically Noteworthy QTc Change From Screening. A similar proportion of patients in the placebo and paroxetine groups had an increased QTcB interval of 960 milliseconds from screening, whereas significantly more patients in the imipramine group experienced this predefined change compared with either paroxetine (p G .003) or placebo (p G .005) groups (Table 4). Similarly, the percentage of patients with a treatmentemergent QTcB prolongation of 30Y60 milliseconds was significantly higher in imipramine-treated patients compared with paroxetine (p G .001) and placebo (p G .001) treatment. In addition, a significantly greater proportion of imipramine-treated patients had a QTcF interval increase of 30Y60 milliseconds compared with
paroxetine-treated patients (p G .027). Although the proportion of patients with an increased QTcB interval 30Y60 milliseconds from screening was higher in the placebo group compared with the paroxetine group (p G .05), the proportion of patients with an increased QTcF interval 30Y60 milliseconds from screening was similar in the paroxetine and placebo groups. Changes in QTcF from screening 960 milliseconds were comparable between the three treatment groups. Clinically Noteworthy Absolute Maximum QTc Values. A significantly greater percentage of patients treated with imipramine experienced an absolute QTcB value of 9440 milliseconds compared with either placebo (p G .001) or paroxetine (p G .003) (Table 4). For all other predefined absolute QTcB and QTcF intervals, there were no differences between treatment
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Potentially Clinically Significant QTc Measurements
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PAROXETINE EFFECTS ON PEDIATRIC ECG
TABLE 4 Noteworthy On-Treatment QTcB and QTcF Interval Signals Defined in Terms of Absolute QTc Intervals or Changes From Baseline Placebo Paroxetine Imipramine (n = 207) (n = 200) (n = 42) Variable No. (%) No. (%) No. (%) Maximum QTcB change from screening, ms 30Y60 960 Maximum QTcF change from screening, ms 30Y60 960 Absolute QTcB interval, ms 9440 9450 9480 9500 Absolute QTcF interval, ms 9440 9450 9480 9500
absolute on-treatment QTcF value 9450 milliseconds (one placebo, one paroxetine). The reviewing cardiologist did not consider these absolute QTcB threshold values to be clinically significant. Other Electrocardiographic Measurements
groups. None of the treatment groups were associated with a QTcB or QTcF value of 9500 milliseconds. Of the 15 patients (4 placebo, 3 paroxetine, and 8 imipramine) who had a potentially clinically significant absolute prolonged QTcB interval (9440 milliseconds), 4 patients (2 placebo, 1 paroxetine, and 1 imipramine) exceeded this threshold at screening and are not considered further here. Of those remaining, 5 (2 placebo, 1 paroxetine, and 2 imipramine) patients had absolute on-treatment QTcB threshold values of 9450 milliseconds. The reviewing cardiologist considered two of these patients to have potentially clinically significant QTcB measurements: one placebo-treated patient (absolute threshold QTcB value of 9450 milliseconds with a 960-millisecond change from screening) and one imipramine-treated patient (absolute threshold QTcB value of 9480 milliseconds with a QTcB change from baseline of 960 milliseconds). Analysis of the QTcF values showed that two adolescent females had an
Heart Rate. Overall, at screening the mean heart rate in the paroxetine group was similar to that in the placebo group but was significantly higher compared with the imipramine group (Table 2; p = .040). At screening, female patients had higher heart rates compared with male patients in the paroxetine group (p = .028). Females in the placebo and paroxetine groups had higher screening heart rates than those in the imipramine group (p = .022 and p = .029, respectively). No difference in heart rate was observed between genders in the placebo and imipramine groups. Children had higher heart rates compared with adolescents at screening in the placebo (p G .001) and paroxetine (p G .001) groups. There was no change in overall mean heart rate between screening and treatment in the paroxetine (0.8 bpm increase from screening) and placebo (0.9 bpm decrease from screening) groups (Table 3). In the imipramine group, however, mean heart rate significantly increased by 21.4 bpm overall compared with screening values (p G .001). This increase was significantly higher compared with the placebo (p G .001) and paroxetine (p G .001) groups. Analysis of the R-R interval at baseline and during treatment reflected and supported the observations for mean heart rate (Tables 2 and 3). PR Interval. Overall, the screening mean PR interval was comparable between placebo and paroxetine groups (Table 2). Patients in the imipramine group had a longer mean PR interval at screening compared with patients in the paroxetine (p G .001) or placebo groups (p G .004). Female patients in the placebo and paroxetine groups had a shorter PR interval compared with females in the screening imipramine group (p = .001 and p G .001, respectively). In the placebo group, children had a shorter mean PR interval compared with adolescents (p = .020). In placebo-treated patients, the mean PR interval significantly increased by 2.3 milliseconds compared with screening (Table 3; p = .028). The mean PR interval increased slightly but not significantly from screening to treatment in the imipramine group (7.6 milliseconds; p = .069). No differences
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24 (11.6)a 3 (1.5)
10 (5.0) 2 (1.0)
16 (38.1)b,c 5 (11.9)d,e
24 (11.6) 3 (1.5)
5 (2.5) 0 (0)
4 (9.5)f 1 (2.4)
4 (1.9) 3 (1.5) 0 (0) 0 (0)
3 (1.5) 2 (1.0) 0 (0) 0 (0)
8 (19.1)d,g 2 (4.8) 1 (2.4) 0 (0)
1 (0.5) 1 (0.5) 0 (0) 0 (0)
2 (1.0) 1 (0.5) 0 (0) 0 (0)
1 (2.4) 0 (0) 0 (0) 0 (0)
p G .05 versus placebo; b p G .0001 versus placebo; c p G .0001 versus paroxetine; d p G .003 versus paroxetine; e p G .005 versus placebo; f p G .027 versus paroxetine; g p G .0006 versus placebo (all determined using analysis of variance between the three treatment groups). a
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KRULEWICZ ET AL.
were seen in the paroxetine group (j1.2 milliseconds; p = .158). Comparison of the difference between ontreatment and screening PR values between treatments showed that imipramine increased the PR interval compared with placebo (p = .028) and paroxetine (p G .001), whereas paroxetine decreased the PR interval compared with placebo (p = .013). QRS Duration. There were no significant differences in the mean QRS duration overall between treatment groups at screening (Table 2). Children had a shorter QRS value compared with adolescents in the screening paroxetine group (p G .001). No changes in the mean QRS duration were observed in either the placebo or paroxetine groups between screening and treatment, but imipramine treatment significantly increased the mean QRS duration by 5.1 milliseconds compared with screening (Table 3; p = .001). The mean change in QRS duration from screening to on-treatment was significantly higher in the imipramine group (5.1-millisecond increase) compared with either placebo (0.5-millisecond increase; p G .001) or paroxetine (0.0 milliseconds; p G .001).
underlying conduction abnormality and further evaluation of this patient by a pediatric cardiologist was recommended. DISCUSSION
In study 1, six patients had treatment-emergent cardiovascular adverse events that led to withdrawal from the study: nodal arrhythmia in one patient on placebo; atrioventricular (AV) block in one patient on paroxetine (investigator assessed causality was possibly related to study medication); and four different imipramine patients with four disparate findings: arrhythmia, abnormal ECG, extrasystoles, and a prolonged QT interval with AV block (investigator assessed causalities were possibly related and related to study medication). No abnormal ECG assessments were observed in study 2, and in study 3, only one patient in the placebo group had an abnormal ECG assessment, as judged by the treating investigator. During the post hoc analysis of these data, it was discovered that one patient in the paroxetine group had an abnormal ECG at screening with evidence consistent with low right atrial rhythm and Wolf-ParkinsonWhite syndrome. These same findings were noted on the ECG performed at the trial end (week 8). Because this was not reported as part of the patient’s initial medical history or as a study adverse event, the principal investigator was notified regarding the possibility of an
This retrospective analysis of ECG interval data from three double-blind, placebo-controlled trials of paroxetine in children and adolescents with MDD or OCD suggested that paroxetine was not associated with prolongation of QTcB or QTcF or other indices of cardiac conduction in this patient population. The majority of patients in the placebo and paroxetine groups experienced no significant changes in ECG intervals between screening and on-treatment measurements. These findings are consistent with results from controlled adult studies, which indicate that paroxetine has no systematic impact on adult cardiac conduction (Boyer and Blumhardt, 1992). This analysis showed that no patient experienced a prolonged QTcB or QTcF value of 9500 milliseconds while on-treatment in any group. Using the clinically noteworthy QTc interval (of 9440 milliseconds), 98.5% of patients receiving paroxetine had a normal QTcB interval compared with 98% in the placebo group and 81% in the imipramine group. Therefore, a prolonged QTc interval only occurred in three outlying patients in the paroxetine and four in the placebo groups, and these cases were not considered to be clinically significant. In the present analysis, imipramine served as a positive control because it is known to significantly increase ECG parameters such as heart rate, QRS duration, and mean change in QTcB between screening and on treatment (Giardina et al., 1979; Gutgesell et al., 1999). As expected, imipramine significantly altered a number of ECG measurements compared with paroxetine or placebo treatment. In the imipramine group, the change in QTcB interval on-treatment was significantly longer compared with screening values, but there was no significant difference in the corresponding mean change in QTcF interval between screening and treatment. The discrepancy between these results may be caused by the increase in heart rate observed in imipramine-treated patients and the slight variation in the way this increase is incorporated into the QTcB and QTcF correction methods. It is also possible that the increase in QTcB interval between screening and imipramine treatment
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Electrocardiographic Adverse Events Reported During the Clinical Trials
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PAROXETINE EFFECTS ON PEDIATRIC ECG
may be associated with the increased QRS duration observed in these patients. The heart rate was unaffected by treatment in the placebo and paroxetine groups; therefore, there was no major discrepancy in results for the QTcB and QTcF intervals within these groups.
Limitations
The retrospective nature of the analysis, particularly with regard to the retrieval of ECG data from study centers from as far back as 1994, is a limitation because ECG data of approximately two thirds of the patients randomized were available for retrieval. Original ECGs were obtained from a number of study sites using different equipment, which may contribute to variability within the data set. Only a single ECG was available at each time point, and none of the ECGs were digitally recorded. Therefore, ECGs had to be digitized before intervals could be annotated and over-read. Six study sites did not return any ECGs for analysis, and data for some patients were excluded if at least one screening and at least one on-treatment ECG were not available or caused by poor overall quality of some ECGs. Some commonly occurring comorbid conditions in children and adolescents with depression or OCD were exclusion criteria for the three studies included in this analysis. In general, no other concomitant pharmacotherapy for psychiatric illness was permissible. Also, patients with clinically significant ECG abnormalities at baseline were to be excluded from these studies. These limitations may therefore affect the ability to generalize the findings to the broader population. Additional studies may be necessary to identify which children may be at increased risk of possible cardiac events. In addition to the studies being short term (8Y10 weeks), no information regarding the relationship between medication dose and/or duration of exposure to medication on ECG tracings was collected in these studies, which further limits the conclusions that can be drawn from these data. Although this represents the largest analysis of cardiovascular functioning in children and adolescents receiving an SSRI to date, statistical comparisons between children and adolescent groups were only made at screening; therefore, any conclusions about age-related treatment differences between these two groups cannot be made. Moreover, despite the large
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sample size, the possibility of rare events cannot be precluded. It should also be noted that the imipramine group only included adolescents, whereas both children and adolescents comprised patients in the placebo and paroxetine groups. It is therefore possible that the observed differences between treatment groups arose because of the varying age of patients; however, the lack of difference observed between paroxetine and placebo appears consistent in children and adolescents.
Clinical Implications
Based on the comparison of cardiac conduction intervals in patients treated with paroxetine and placebo, these results suggest that paroxetine is unlikely to cause clinically significant prolongation of these intervals in pediatric patients. These data were gathered retrospectively from three previously completed clinical trials assessing the efficacy, tolerability, and short-term safety of paroxetine. These observations are consistent with those of previous studies investigating the cardiovascular effects of paroxetine in adult patients with depression (Edwards et al., 1989; Kuhs and Rudolf, 1990). The current analyses support published guidelines concerning ECG monitoring in children and adolescents, namely, that extensive ECG monitoring is not required for patients receiving paroxetine (Francis, 2002; Gutgesell et al., 1999). ECG monitoring is indicated, however, if paroxetine is coprescribed with drugs that cause QTc prolongation or that share the same metabolic pathways or where clinically indicated based on individual and familial history. Findings from this retrospective analysis address the cardiovascular effects of paroxetine in the pediatric population. The use of antidepressants, including paroxetine, in patients younger than 18 years old has been scrutinized by regulatory authorities because of concerns of increased risks of suicidal ideation, suicide attempts, or self-harm. Recently, a U.S. Food and Drug Administration advisory committee concluded that there is an increased risk of suicidality in children and adolescents receiving antidepressants. As a result, the U.S. Food and Drug Administration required antidepressants to carry ‘‘black box’’ warnings about the risk of increased suicidal tendencies and careful monitoring of children receiving SSRIs. Paroxetine is not approved for use in pediatric patients.
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Disclosure: Mr. Krulewicz, Drs. Carpenter, Fong, Horrigan and Lipschitz are employees of GlaxoSmithKline and may own stock in the company. Dr. Perera is a former employee of GlaxoSmithKline and may own company stock. Dr. Wagner receives active research support from Eli Lilly, National Institute of Mental Health, and Organon and is a consultant to Abbott Laboratories, Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Janssen, Jazz Pharmaceuticals, Novartis, Ortho-McNeil, Otsuka, Pfizer, and the National Institute of Mental Health Advisory Council. REFERENCES
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