3.2.2.1 Primary outcome
NPI total score change
11 trials including 4 AAPs(aripiprazole, risperidone, olanzapine and quetiapine) reported NPI total scores changes. The NMA showed there was no statistically significant difference between these AAPs and placebo or between these AAPs(Table 1). The SUCRA showed aripiprazole was the most likely to improve NPI total scores(84.3%),followed by risperidone(71.5%), olanzapine(52.8%), quetiapine(27.0%) and placebo(14.3%) (Supplementary10).
Table 1
League Table of NPI total score changea
Aripiprazole
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|
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|
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-2.20 (-7.82, 3.15)
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Olanzapine
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|
|
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-4.16 (-8.45, 0.12)
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-1.96 (-5.35, 1.66)
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Placebo
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|
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-3.64 (-8.92, 1.95)
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-1.44 (-5.65, 3.30)
|
0.50 (-2.73, 4.08)
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Quetiapine
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|
-1.04 (-7.00, 5.11)
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1.14 (-2.91, 5.64)
|
3.10 (-1.08, 7.53)
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2.60 (-2.42, 7.54)
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Risperidone
|
a Comparisons are based on standardized mean differences (SMDs) between treatments. |
NPI-psychosis total score change
8 trials including 5 AAPs(pimavanserin, aripiprazole, risperidone, olanzapine and quetiapine) reported NPI-psychosis total scores changes. The NMA showed there was no statistically significant difference between these AAPs and placebo or between these AAPs (Table 2). The SUCRA showed pimavanserin had the highest probability of NPI-psychosis improvement(84.6%), followed by aripiprazole(68.5%), olanzapine (48.4%), ,risperidone(38.3%), placebo(30.8%)and quetiapine(29.4%)(Supplementary10).
Table 2
League Table of NPI-psychosis total score changea
Aripiprazole
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-0.53 (-2.61, 1.51)
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Olanzapine
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0.91 (-2.12, 3.93)
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1.43 (-1.61, 4.49)
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Pimavanserin
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|
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-0.88 (-2.34, 0.54)
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-0.36 (-1.83, 1.12)
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-1.79 (-4.48, 0.87)
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Placebo
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|
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-1.24 (-4.49, 1.97)
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-0.71 (-3.96, 2.53)
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-2.16 (-6.13, 1.84)
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-0.35 (-3.26, 2.55)
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Quetiapine
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-0.81 (-3.48, 1.80)
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-0.28 (-2.48, 1.88)
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-1.72 (-5.21, 1.71)
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0.07 (-2.15, 2.26)
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0.43 (-3.22, 4.06)
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Risperidone
|
a Comparisons are based on standardized mean differences (SMDs) between treatments. |
Discontinuation rate due to adverse event
20 trials including 7 AAPs reported proportion of discontinuation due to any adverse event. The network meta-analyses showed olanzapine had higher discontinuation rate due to adverse event than placebo(OR 2.52,95%CI 1.62 to 4.27), pimavanserin(OR 3.14,95%CI 1.06 to 10.18),quetiapine(OR 2.93,95%CI 1.47 to 6.43) and risperidone(OR 2.12,95%CI 1.31 to 3.89)(Table 3).According to SUCRA, quetiapine had the highest probability of tolerability(77.5%), followed by pimavanserin(74.7%), placebo(68.3%), amisulpride(61.4%), risperidone(49.6%), aripiprazole(40.0%), brexpiprazole(21.4%) and olanzapine(7.1%)(Supplementary10).
Table 3
League Table of discontinuation rate due to adverse eventa
Amisulpride
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0.69 (0.10, 4.46)
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Aripiprazole
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0.49 (0.06, 3.31)
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0.70(0.24, 1.85)
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Brexpiprazole
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0.38 (0.06, 2.25)
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0.54 (0.24, 1.16)
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0.77 (0.30, 2.06)
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Olanzapine
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|
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1.20 (0.15, 8.87)
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1.70 (0.52, 5.82)
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2.43 (0.70, 9.66)
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3.14 (1.06, 10.18)b
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Pimavanserin
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0.96 (0.15, 5.53)
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1.36 (0.76, 2.59)
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1.95 (0.90, 4.75)
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2.52 (1.62, 4.27) b
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0.80 (0.28, 2.24)
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Placebo
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|
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1.11 (0.17, 6.96)
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1.58 (0.71, 3.74)
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2.27 (0.89, 6.62)
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2.93 (1.47, 6.43) b
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0.93 (0.29, 3.04)
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1.16 (0.67, 2.03)
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Quetiapine
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|
0.81 (0.13, 4.47)
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1.15 (0.57, 2.48)
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1.64 (0.69, 4.41)
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2.12 (1.31, 3.89) b
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0.67 (0.23, 2.06)
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0.84 (0.58, 1.26)
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0.73 (0.38, 1.38)
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Risperidone
|
a Comparisons are based on odds ratio(OR) between treatments. |
b Significant results |
3.2.2.3 Safety outcome
Adverse event
14 trials including 6 AAPs(amisulpride, brexpiprazole, olanzapine, pimavanserin, quetiapine and risperidone) reported proportion of adverse event. The NMA showed there was no statistically significant difference between these AAPs and placebo or between these AAPs(Supplementary9). The SUCRA showed placebo was most likely to be the first considering lower proportion of adverse event(77.9%), followed by amisulpride(61.2%), quetiapine(53.9%), pimavanserin(53.7%), risperidone(48.3%), brexiprazole(37.1%) and olanzapine(17.9%)(Supplementary10).
Serious adverse event
14 trials including 7 AAPs reported serious adverse event. The NMA suggested there was no statistically significant difference between the seven AAPs or between them and placebo(Supplementary9). The SUCRA showed placebo was ranked first(83.0%) followed by risperidone(79.5%), olanzapine(66.6%), aripiprazole(51.4%), quetiapine(44.4%), pimavanserin(38.4%), brexpiprazole(32.0%) and amisulpride(4.6%)(Supplementary10).
Mortality
13 trials including 5 AAPs(aripiprazole, olanzapine, pimavanserin, quetiapine, risperidone) reported mortality. The NMA indicated there was no statistically significant difference between these AAPs or between them and placebo(Supplementary9). According to the SUCRA, placebo had the highest probability of safety on mortality(79.7%), followed by pimavanserin(63.5%), risperidone(59.8%), quetiapine(45.5%), olanzapine(31.4%) and apripiprazole(20.0%)(Supplementary10).
MMSE change
12 trials including 5 AAPs(amisulpride, aripiprazole, olanzapine, quetiapine and risperidone) reported MMSE changes. The NMA showed there was no statistically significant difference between these AAPs and placebo or between these AAPs(Supplementary9).The SUCRA showed amisulpride had the least effect on cognitive function(93.7%),followed by placebo(58.5%), risperidone(47.2%), olanzapine(43.4%), quetiapine(41.5%), aripiprazole(15.7%)(Supplementary10).
CVAEs
10 trials including 4 AAPs(aripiprazole, olanzapine, quetiapine and risperidone) reported CVAEs. The NMA showed olanzapine had higher risk of CVAEs than placebo(OR5.03,95%CI 1.18 to 23.92) (Supplementary9). The SUCRA indicated quetiapine had the highest probability of safety on CVAEs(85.1%), followed by placebo(81.9%), risperidone(38.9%), aripiprazole(29.0%) and olanzapine(15.2%)(Supplementary10).
Falls, fracture, or injury
17 trials including 6 AAPs(aripiprazole, brexpiprazole, olanzapine, pimavanserin, quetiapine, risperidone) reported falls, fracture or injury. The NMA showed there was no statistically significant difference between these AAPs and placebo. However, olanzapine had higher risk than quetiapine(OR 1.51, 95%CI 1.03 to 2.3) and risperidone(OR 1.47, 95%CI 1.05 to 2.09) (Supplementary9).The SUCRA showed brexpiprazole had the highest probability of safety on falls, fracture, or injury(77.4%), followed by quetiapine(70.2%), risperidone(68.3%), placebo(43.4%), pimavanserin(41.7%) aripiprazole(38.4%) and olanzapine(10.6%)(Supplementary10).
Somnolence or sedation
17 trials including 6 AAPs(amisulpride, aripiprazole, brexpiprazole, olanzapine, quetiapine, risperidone) reported somnolence or sedation rate. The NMA showed aripiprazole, olanzapine, quetiapine and risperidone had higher risk of somnolence or sedation than placebo(OR4.75,95%CI 1.82 to 15.56) (OR3.38,95%CI 2.25 to 5.58), (OR3.68,95% 2.32 to 6.36) (OR 2.09,95%CI 1.53 to 2.96). Olanzapine and quetiapine had higher risk than brexpiprazole and risperidone.Aripiprazole had higher risk than brexpiprazole too(Supplementary9). The SUCRA showed placebo had the highest probability of safety on somnolence or sedation(97.6%), followed by brexpiprazole(82.2%),risperidone(63.0%),olanzapine(32.0%),amisulpride(32.0%) ,quetiapine(26.3%) and aripiprazole(16.9%)(Supplementary10).
Body weight change
10 trials including 5 AAPs(aripiprazole,olanzapine,pimavanserin,quetiapine,risperidone) reported body weight changes. The NMA showed olanzapine had greater change of body weight than placebo(SMD0.48,95%CI 0.03 to 1.07),quetiapine(SMD0.78,95%CI0.19 to 1.45) and risperidone(SMD0.56,95%CI 0.01 to 1.20) (Supplementary9). The SUCRA showed quetiapine had the highest probability of safety on body weight change(87.6%), followed by risperidone(67.0%), placebo(58.7%), aripiprazole(43.0%), pimavanserin(26.9%) and olanzapine(16.8%)(Supplementary10).
Extrapyramidal symptoms(EPSs)
16 trials includine 6 AAPs(amisulpride, aripiprazole, brexpiprazole, olanzapine, quetiapine, risperidone) reported proportion of EPSs. The NMA showed olanzapine and risperidone had higher risk of EPSs than placebo(OR3.09,95%CI1.44 to 7.72) (OR2.18,95%CI1.42 to 3.82) and quetiapine(OR5.14,95%CI 2.17 to 15.30)(OR3.65,95%CI 1.87 to 8.46).Brexpiprazole had higher risk than quetiapine(OR3.08,95%CI1.07 to 9.92) (Supplementary9). The SUCRA showed quetiapine had the highest probability of safety on EPSs(95.8%), followed by placebo(74.1%), aripiprazole(53.3%), amisulpride(52.8%), brexpiprazole(37.2%), risperidone(27.1%) and olanzapine(9.7%)(Supplementary10).
Respiratory infection
8 trials including 6 AAPs (aripiprazole, brexpiprazole, olanzapine, pimavanserin, quetiapine, risperidone) reported proportion of respiratory infection. The NMA showed there was no statistically significant difference between these AAPs or between them and placebo(Supplementary9). The SUCRA showed risperidone had the highest probability of safety on respiratory infection(71.9%), followed by placebo(66.4%), quetiapine(64.2%), pimavanserin(58.0%), aripiprazole(44.1%), olanzapine(24.8%), brexpiprazole(20.6%)(Supplementary10).
Peripheral edema
7 trials including 5 AAPs (aripiprazole, olanzapine, pimavanserin, quetiapine, risperidone) reported proportion of peripheral edema. The NMA showed risperidone had higher risk of peripheral edema than placebo(OR2.48,95%CI1.13 to 6.1) (Supplementary9). The SUCRA showed quetiapine had the highest probability of safety on peripheral edema(78.3%), followed by placebo(76.6%), aripiprazole(70.0%), olanzapine(33.9%), risperidone(26.9%) and pimavanserin(14.4%)(Supplementary10).
QTc interval increase rate
7 trials including 5 APPs (aripiprazole, brexpiprazole, olanzapine, quetiapine, risperidone) reported a proportion of QTc interval increase. The NMA showed there was no statistically significant difference between these AAPs or between them and placebo(Supplementary9). The SUCRA showed olanzapine had the highest probability of safety on QTc interval increase(81.2%), followed by risperidone(77.3%), quetiapine(48.7%), brexpiprazole(48.1%), placebo(34.1%) and aripiprazole(10.6%)(Supplementary10).