Supplementary Table 1.Studies assessing QTc prolongation and or torsade de pointes associated with the second-generation antipsychotics considered to carry the risk of these complications
Drug / TQT / QTc prolongation-specific studies / Toxicology / Efficacy safety / Case reportsAmisulpride / None / 1[16] / 2[17;18] / 1[19] / 10[20-25]
Clozapine / None / 5[16;26-29] / 1[30] / 6[31-36] / 5[37-41]
Iloperidone / 1[42] / None / None / 3[43-45] / None
Olanzapine / 1[46;47] / 11[16;28;48-56] / None / 12[57-68] / 6[69-74]
Paliperidone / None / 2[75;76] / None / 2[77;78] / None
Quetiapine / 2[42;46] / 6[48;51;54-56;75] / 3[79-81] / 1[82] / 16[24;83-96]
Risperidone / 1[46] / 14[29;48;51-55;76;97-102] / 1[103] / 9[33;34;45;78;104-108] / 13[1;70;85;109-118]
Sertindole / None / 3[16;119;120] / None / 5[31;61;106;107;121] / None
Ziprasidone / 2[42;46;47] / 5[122-126] / 1[127] / 28[32;33;35;36;44;57-60;128-146] / 13[147-157]
Supplementary Table 2.Studies assessing QTc prolongation and or torsade de pointes associated with the second-generation antidepressants considered to carry the risk of these complications
Drug / TQT / QTc studies / Toxicology / Efficacy safety / Case reportsCitalopram / 1[8] / 3[13;158;159] / 7[160-166] / 1[167] / 16[69;87;112;168-180]
Escitalopram / 1[8] / None / 3[162;163;181] / 2[182;183] / 6[184-189]
Fluoxetine / None / 4[158;159;190;191] / 1[164] / None / 9[192-200]
Mirtazapine / None / 1[158] / 2[165;166] / None / None
Paroxetine / None / 5[158;159;201-203] / 1[164] / 2[204;205] / None
Sertraline / None / 3[158;159;206] / 1[164] / 3[207-209] / 2[210;211]
Venlafaxine / None / 3[158;212;213] / 4[165;166;214;215] / None / 5[87;94;216-218]
Supplementary Table 3. Summary of efficacy and safety studies of the nine second-generation antipsychotics (amisulpride, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, and ziprasidone) considered to carry the risk of QTc interval prolongation and torsade de pointes (TdP).
Study and drug(s) involved / Brief study description / Major findings pertinent to QTc interval1 / Coulouvrat and Dondey-Nouvel (1999)[19]
Amisulpride
Pooled analysis / Data were pooled from 11 clinical studies of amisulpride. A total of 341 patients treated with amisulpride, 91 patients treated with risperidone and 80 patients treated with haloperidol had at least one electrocardiogram (ECG) during treatment. QTc interval prolongation was defined as >450 msec in men and >470 msec in women. / The incidences of prolonged QTc interval were not statistically significant between amisulpride (3.5%), risperidone (3%) and haloperidol groups (1%). Increase in QTc interval ≥60 msec was observed in 1% of amisulpride treated patients but in none of patients treated with risperidone or haloperidol.
2 / Sacchetti et al (2009)[36]
Clozapine and ziprasidone / In this 18-week, randomized, flexible-dose, double-blind, double-dummy study, treatment-refractory schizophrenia patients were randomized to ziprasidone (80–160 mg/day, N=73) or clozapine (250–600 mg/day, N=74). ECGs were obtained at screening, visit 1, at months 2 and 3, and at the end of the study. / Mean change in Bazett’s formula-corrected QT interval (QTcB) was comparable for ziprasidone (6.0 msec) andclozapine (−3.6 msec) groups. Three patients (4.5%) in the ziprasidone group and 10 (14.1%) in the clozapine group had QTcB values ≤450 msec at screening and ≥450 msec at endpoint. One clozapine patient had a QTcB value ≤500 msec at screening and >500 msec at endpoint.
3 / Muscatello et al (2013)[35]
Clozapine and ziprasidone / A 16-week, double-blind trial in which adult patients with residual schizophrenia were randomized to either ziprasidone 80 mg/day (N=20) or placebo (N=20) add-on therapy. All patients had been on clozapine monotherapy at the highest tolerable range (350-600 mg/day) for ≥1 year. Monitoring included obtaining an ECG at baseline, 4, 8, and 16 weeks. / For ziprasidone group, QTcB interval increased from 403.3 msec at baseline to 407.6 msec at week 16. The respective change in the placebo group was a decrease from 408.2 mecs to 405.4 msec. The difference between two groups was not significant but the QTcB prolongation within ziprasidone group was significant.
4 / Nielsen et al (2012)[31]
Clozapine and sertindole / A 12-week, double-blind, randomized, placebo-controlled study in which adult patients with schizophrenia with poor response to clozapine treatment for ≥6 months were randomized to either sertindole or placebo (N=25 each) add-on treatment. ECGs were obtained at baseline and after 3 and 12 weeks. Both QTcB and Fridericia’s formula-corrected QT interval(QTcF) were assessed. / Clozapine dose was similar for both groups. Initial dose of sertindole was 4 mg and increased by 4 mg every 4 days until the target dose of 16 mg was achieved. Treatment with sertindole was associated with a mean of 12 msec increase (0 msec change in placebo group; P <0.03) in the electronically assigned QTcB, but there were no significant changes in manually-calculated QTcF interval.
5 / Henderson et al (2009)[32]
Clozapine, olanzapine and ziprasidone / In this 6-week, open label trial, ziprasidone 160 mg/day was added to stable dose of 10 olanzapine-treated and 11 clozapine-treated adult patients with metabolic morbidity. / The mean QTc increased significantly from baseline (417 msec) to 2 weeks (430 msec) but the difference was not significant at 6 weeks (420 msec).
6 / Zink et al (2009)[33]
Clozapine, risperidone and ziprasidone / In this 6-week, open-label study, adult patients with partial response to clozapine were randomized to augmentation with ziprasidone (n = 12) or risperidone (n = 12). Safety assessment included ECG at baseline and after 2, 4 and 6 weeks of augmentation. / Clozapine-ziprasidone patients experienced a significant increase of QTcF interval from 387.7 to 403.2 msec (P=0.043). It did not change significantly in the clozapine-risperidone group. The maximum observed QTcF interval was 423.5 msec in the clozapine-ziprasidone group and 417.7 msec in the clozapine-risperidone group.
7 / Anil Yagcioglu et al (2005)[34]
Clozapine and risperidone / In this 6-week double-blind study, patients with schizophrenia partially responsive to clozapine were randomized to risperidone (N=16) up to 6 mg/day or placebo (N=14). ECGs were done at baseline and study endpoint. / The mean change in QTcB from baseline to endpoint was -10.6 msec (from 440.9 msec to 430.3 msec) in risperidone group and 13.2 msec (from 436.8 msec to 450 msec) in the placebo group (not significant in both groups). No patient in the risperidone group and 3 patients in the placebo experienced clinically significant increase in QTc defined as a QTc ≥450 msec and a 10% increase from baseline.
8 / Kane et al (2008)[43]
Haloperidol and iloperidone / In this study, data were pooled from 3 prospective multicenter studies, each with 6-week stabilization followed by 46-week double-blind maintenance phases. Patients (mean age 34.7 years, range 18-69 years; 63% males) were randomized to iloperidone 4 to 16 mg/day or haloperidol 5 to 20 mg/day. / Of 1644 patients randomized and 1326 completing the 6-week phase, 489 were included (iloperidone, N=371; haloperidol, N=118) in the safety analysis. Treatment with iloperidone and haloperidol produced similar changes from baseline in QTcF. At week 6, the changes were 3.2 msec for iloperidone and 4.0 msec for haloperidol. At end point, the respective values were 10.3 msec and 9.4 msec.
9 / Cutler et al (2008)[44]
Iloperidone and ziprasidone / This randomized, placebo-controlled, multicenter study comprised of a 1-week titration period and a 3-week double-blind maintenance period. Eligible adult patients (N=593) were randomized to iloperidone (24 mg/day by day 7), ziprasidone (160 mg/day by day 7) as an active control, or placebo in a 2:1:1 ratio. Safety assessment included obtaining ECGs. QT interval was corrected for heart rate (HR) using Fridericia’s correction. / Mean changes in QTcF from baseline to day 14 (11.4 and 11.3 msec with iloperidone and ziprasidone, respectively) and day 28 (7.0 and 5.2 msec in the iloperidone and ziprasidone groups, respectively) were significant versus placebo (P<0.001 on both occasions). Mean maximum changes in the QTcF interval were similar in iloperidone (16.2 msec) and ziprasidone (12.3 msec) patients and significantly greater than those with placebo (-2.4 msec; P <0.001 for both). No patient had a change in QTcF interval from <500 msec at baseline to ≥500 msec. Two iloperidone patients and 1 ziprasidone patient experienced ≥15% increases in the QTcF interval.
10 / Weiden et al (2008)[45]
Haloperidol, iloperidone and risperidone / This study performed a pooled analysis of 3 phase-2, short-term acute schizophrenia studies to assess the safety of iloperidone in adults. The safety population included 440 patients on placebo, 463 patients on iloperidone 4 to 8 mg/day, 456 patients on iloperidone 10 to 16 mg/day, 125 patients on iloperidone 20 to 24 mg/day, 118 patients on haloperidol 15 mg/day, and 306 patients on risperidone 4 to 8 mg/day. ECGs were performed at pre-specified intervals. QTc was calculated using Fridericia’s formula. / The QTcF interval increased across all treatment groups. The least squares (LS) mean changes in QTcF from baseline to end point were 2.9 msec, 3.9 msec, and 9.1 msec for iloperidone 4 to 8 mg/day, 10 to 16 mg/day, and 20 to 24 mg/day, respectively (all P<0.05). Patients treated with haloperidol showed an LS mean increase of 5.0 msec in QTcF (P<0.05), whereas the increase with risperidone (0.6 msec) was not significant. Patients taking placebo showed no mean change in QTcF intervals. No deaths or serious arrhythmias attributable to QTc prolongation occurred in these studies.
11 / Ou et al (2013)[57]
Olanzapine and ziprasidone / A 6-week, multicenter, open-label trial in which 260 patients (age range 18-45 years) with schizophrenia were randomly and equally assigned to receive either ziprasidone or olanzapine. The study primarily aimed at comparing metabolic effects of ziprasidone and olanzapine. QTc interval was monitored as a safety measure. / The mean QTc interval at baseline was 401.8 msec for ziprasidone group and 396.8 msec for olanzapine group. The mean daily dosages were 138.2 mg for ziprasidone and 19.0 mg for olanzapine. By 6th week, mean QTc interval increased significantly for the ziprasidone group (16.9 msec) compared with the olanzapine group (6.2 msec). No patient in either group exhibited a QTc interval ≥500 msec.
12 / Simpson et al (2005)[58]
Olanzapine and ziprasidone / In this 6-month blinded, flexible-dose study, adult patients with schizophrenia or schizoaffective disorder received either olanzapine (N=55) or ziprasidone (N=44). At 6 months, mean doses for ziprasidone and olanzapine were 135.2 mg/day (range 78-162 mg/day) and 12.6 mg/day (range 5–15 mg/day), respectively. / The mean change in QTcB from baseline to endpoint was 1.1 msec (from 406 msec to 407.1 msec) in the ziprasidone group and -5.3 msec (from 399.7 msec to 394.4 msec) in the olanzapine group. Observed QTc mean changes were not statistically significant between the two treatment groups. No patient in the study had a QTc ≥500 msec.
13 / Brown and Estoup (2005)[60]
Olanzapine and ziprasidone / This study performed a retrospective chart review of 191 randomly selected patents being treated with ziprasidone or olanzapine to primarily assess metabolic complications. / Baseline and follow-up QTc interval was available for 23 olanzapine and 39 ziprasidone-treated patients. No significant differences for the QTc interval were observed for either agent.
14 / Simpson et al (2004)[59]
Olanzapine and ziprasidone / In this 6-week, multicenter, double-blind, flexible-dose trial, patients were randomized to ziprasidone (N=136; mean age 37.7 years, range 9-55 years; mean dose 129.9 mg/day) or olanzapine (N=133; mean age 37.6 years, range 8-59 years; mean dose 11.3 mg/day). ECGs were obtained at screening and at the end of week 6 or at endpoint. / QTc intervals were calculated by using the formula QTc=QT/RR0.4, where RR=HR/60.The mean change from baseline for QTc interval was 6.08 msec in the ziprasidone group and 0.52 msec for the olanzapine group (no significant difference between groups). No patient in either group exhibited a QTc interval ≥500 msec.
15 / Kwon et al (2012)[61]
Olanzapine and sertindole / A 12-week, double-blind study in which adult patients with schizophrenia who had responded poorly to previous treatment were randomized to receive sertindole (N=196; mean dose 17 mg/day) or olanzapine (N=193; mean dose 16 mg/day). The study aimed at comparing the efficacy and safety of the two drugs. QTc interval was monitored as a safety measure. / The incidence of QTcF prolongation was significantly higher in the sertindole group (26.5%) than the olanzapine group (5.7%). The mean QTcF change from baseline to the last assessment was 24.7 msec in the sertindole group and 3.5 msec in the olanzapine group. Five patients (2.6%) in the sertindole group had a QTcF interval >500 msec. There were no serious cardiac adverse events in either treatment group.
16 / Czekalla et al (2001)[62]
Olanzapine / This study analyzed ECGs obtained as part of the safety assessment during 4 randomized, controlled clinical trials (N=2700) comparing olanzapine with placebo, haloperidol, and risperidone in acutely psychotic patients. The study focused only on QTc interval changes specific to olanzapine treatment. A QTc interval ≥430 msec was considered as prolonged. / Based on their longest QTc interval, 1.9% of olanzapine treated patients had a QTC interval ≥450 msec during olanzapine treatment versus 1.7% of patients at baseline. Similar number of olanzapine-treated patients had a maximum QTc interval increase (17.9%) and decrease (17.8%) in QTc interval of ≥30 msec. In two out of 1555 patients endpoint QTc interval increased by ≥70 msec. 8 out of 1424 patients showed multiple and consistent post-baseline and endpoint values ≥430 msec with 4 of these having values ≥450 msec and the greatest value being 462 msec.
17 / Street et al (2001)[63]
Olanzapine / This efficacy and safety study of olanzapine included 105 patients with possible/probable Alzheimer’s disease related psychosis. Following a double-blind, 6-week exposure to fixed-dose olanzapine (5, 10, or 15 mg/day), patients entered an additional 18-week, open-label, flexible-dose treatment. / Baseline was defined from the start of the extension phase. ECG was obtained at baseline and at study end. QTc interval decreased slightly by 0.94 msec from baseline to endpoint.
18 / Wright et al (2001)[64]
Haloperidol and olanzapine / Hospitalized adult patients with schizophrenia received one to three intramuscular (IM) injections of olanzapine, 10 mg, IM haloperidol, 7.5 mg, or IM placebo over a 24-hour period for acute agitation. Safety monitoring included obtaining ECGs. / At 24 hours, there were no significant QTc interval changes from baseline (mean=–3.0 msec for olanzapine; mean=–1.2 msec for haloperidol; mean=–3.7 msec for placebo) or significant between-group differences for olanzapine versus haloperidol, or for olanzapine versus placebo).
19 / Breier et al (2002)[66]
Haloperidol and olanzapine / In this open-label study, recently hospitalized acutely agitated patients with schizophrenia (N=270) were randomized to receive 1 to 3 IM injections of olanzapine (2.5, 5.0, 7.5, or 10.0 mg), haloperidol (7.5 mg), or placebo within 24 hours. Safety monitoring included obtaining ECGs. QTcB interval ≥430 msec for males and ≥450 msec for females was considered clinically significant. / QTcB interval changed slightly and insignificantly from baseline to 24-hour endpoint in all treatment groups. The incidence of clinically significant QTcB interval was significantly higher in the olanzapine 5 mg (9.8%), haloperidol (14.3%) and placebo (19%) groups than the olanzapine 2.5 mg (0%) group, and was significantly higher in the placebo group (19%) than the olanzapine 10 mg (7.8%) group. No patient experienced QTc interval >500 msec.
20 / Lindborg et al (2003)[65]
Haloperidol and olanzapine / Databases in this analysis of treatment of agitated patients included: placebo-controlled [two schizophrenia and one bipolar mania trials (n=565)]; haloperidol-controlled [two schizophrenia trials (n=482)]; and geriatric placebo-controlled [1 dementia trial (n=204)]. Patients received 1-3 injections of IM (IM) olanzapine (2.5-10 mg/injection), IM haloperidol (7.5 mg/injection), or IM placebo. ECGs were obtained before and after the injections. / At 2 and 24 hours after IM olanzapine treatment, the mean QTc interval decreased approximately 3 msec from baseline in the placebo- and haloperidol-controlled databases. When there was a statistically significant difference between IM olanzapine and IM placebo, QTcB intervals decreased during treatment with IM olanzapine and increased with IM placebo. The incidences of prolonged (endpoint ≥ 99th percentile of healthy adults or ≥ 500 msec) or lengthened (increase ≥ 60 msec) QTc intervals during treatment with IM olanzapine (<3% placebo- and haloperidol-controlled databases, <12% geriatric placebo-controlled database) were never significantly greater than the comparators.
21 / Meehan et al (2001)[67]
Lorazepam and olanzapine / In this study, 201 adult agitated patients with bipolar mania were randomly assigned to receive one to three injections of olanzapine (10 mg, first two injections; 5 mg, third injection), lorazepam (2 mg, first two injections; 1 mg, third injection), or placebo (placebo, first two injections; olanzapine, 10 mg, third injection) within a 24-hour period. Safety monitoring included obtaining ECGs. / There were no significant differences among treatment groups for the QTc interval at 2 hours after the first injection (olanzapine, -2.31 msec; lorazepam, 5.34 msec; placebo, -3.24 msec) or 24 hours (olanzapine,-5.06 msec; lorazepam, -1.80 msec; placebo, -2.57 msec). Pair-wise comparisons found a significant difference between olanzapine and lorazepam ( P=0.032) but not between olanzapine and placebo at 2 hours after the first injection. At 24 hours after the first injection, there was no difference between olanzapine and lorazepam nor olanzapine and placebo.
22 / Meehan et al (2002)[68]
Lorazepam and olanzapine / This was a multicenter, randomized, double-blind, placebo-controlled parallel study. Patients >50 years old with dementia and agitation were randomized to receive IM olanzapine 2.5 mg, IM olanzapine 5.0 mg, IM lorazepam 1.0 mg and IM placebo. Safety assessment included obtaining ECGs at screening and endpoint (both 2 hour and 24 hour post first injection, and/or upon discontinuation after randomization). / QTc interval decreased significantly 2-hour post-injection in the lorazepam group. It also decreased significantly 24-hour post-injection in the IM olanzapine 2.5 mg group but increased significantly in the placebo group. One patient (1.5%) in the IM olanzapine 2.5 mg group. two patients (3.3%) in the IM olanzapine 5 mg group, three patients (4.7%) in the lorazepam group, and three patients (4.8%) in the placebo group during the 24-hour period had a QTc interval ≥500 msec. The difference between groups was not significant.
23 / Meltzer et al (2008)[77]
Paliperidone Extended-Release (ER) / The study performed pooled analysis of 3 similarly designed 6-week, multicenter, double-blind, randomized, fixed-dose, placebo-controlled studies of paliperidone ER in 1326 adult patients with acute schizophrenia. In each of these studies, ECG was obtained at baseline, days 4, 8, 15, 29, 36, 43, and during a post-study visit (day 50). / Least squares mean differences in linear derived QTc (QTcLD) between placebo and all paliperidone ER treatment groups was <4 msec. There were no clinically relevant differences between the proportions of patients who had a normal QTc (<450 msec) at baseline and a maximum post-baseline QTc value of >450 msec and <480 msec. None of the patients from all groups had a QTcLD ≥480 msec.
24 / Gopal et al (2013)[78]
Paliperidone and risperidone / A post hoc analysis of the risperidone and paliperidone clinical trials database (Johnson & Johnson®-sponsored 64 placebo- or active-controlled studies of 11096 patients) to estimate the risk of sudden death, cardiovascular events, and cerebrovascular events during treatment. For risperidone studies, the duration ranged from 3 to 8 weeks for the oral formulation and was 12 weeks for the parenteral formulation. Study duration for paliperidone studies ranged from 6 to 12 weeks for oral formulation and from 9 to 13 weeks for parenteral formulation. Studies were for a broad range of indications. Treatment emergent adverse events were identified based on 7 pre-specified Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) suggestive of medically important events observed before impending cardiovascular death. ECGs were evaluated for QT interval by readers blinded to treatment. QT interval was corrected for HR using the Fridericia’s formula. / Across the placebo-controlled studies, the adult mean modal daily dose was 3.4 mg (range 0.25 to 16 mg) for risperidone and 8.5 mg (range 0.25 to 16 mg ) for paliperidone Risk in the risperidone/paliperidone pooled group was significantly increased compared to placebo for syncope, tachycardia, palpitations, peripheral edema, dysarthria, and transient ischemic attack. Incidence of death related to cardiovascular events was low and similar across groups. Incidence of QTcF prolongation/TdP was 1.8% in the risperidone/paliperidone group, 0.9% in the placebo group and 1.9% in the active control group. In an analysis of maximum QTcF increase from baseline, more risperidone- and paliperidone-treated patients showed increases of 30 to 60 msec, versus placebo, in both the younger than 30 and older than 74 years age groups, and more risperidone-treated patients aged 30 to 74 years showed increases greater than 60 msec, versus placebo. More elderly patients (age >74 years) versus younger patients (age <30 and 30-74 years) treated with risperidone/paliperidone experienced a maximum QTcF increase of between 30 and 60 msec and 60 msec from baseline.