Benzodiazepines for psychosis-induced aggression or agitation

188 Pages·2013·0.97 MB·English

Benzodiazepines for psychosis-induced aggression or agitation
(Review)
GilliesD, SampsonS,Beck A, Rathbone J
ThisisareprintofaCochranereview,preparedandmaintainedbyTheCochraneCollaborationandpublishedinTheCochraneLibrary
2013,Issue9
http://www.thecochranelibrary.com
Benzodiazepinesforpsychosis-inducedaggressionoragitation(Review)
Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAINLANGUAGESUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARYOFFINDINGSFORTHEMAINCOMPARISON . . . . . . . . . . . . . . . . . . . 3
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Figure1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Figure2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Figure4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
ADDITIONALSUMMARYOFFINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 27
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
AUTHORS’CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
CHARACTERISTICSOFSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
DATAANDANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Analysis1.1.Comparison1BENZODIAZEPINESvsPLACEBO,Outcome1Globalimpression:1.noimprovement. 102
Analysis1.2.Comparison1BENZODIAZEPINESvsPLACEBO,Outcome2Globalimpression:2.needforadditional
medication. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Analysis1.3.Comparison1BENZODIAZEPINESvsPLACEBO,Outcome3Globalimpression:3.sedation. . . 103
Analysis1.4.Comparison1BENZODIAZEPINESvsPLACEBO,Outcome4Globalimpression:4.averagechangescore
(CGI-S,high=worse). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Analysis1.5.Comparison1BENZODIAZEPINESvsPLACEBO,Outcome5Behaviour:1.averagechangescore(ABS,
high=worse). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Analysis1.6.Comparison1BENZODIAZEPINESvsPLACEBO,Outcome6Mentalstate:1.averagechangescore
(PANSS,high=worse). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Analysis1.7.Comparison1BENZODIAZEPINESvsPLACEBO,Outcome7Mentalstate:2.averagechangescore
(PANSS-excitedcomponent,high=worse). . . . . . . . . . . . . . . . . . . . . . . . 105
Analysis1.8.Comparison1BENZODIAZEPINESvsPLACEBO,Outcome8Adverseeffects/events:1.extrapyramidal
symptoms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Analysis1.9.Comparison1BENZODIAZEPINESvsPLACEBO,Outcome9Adverseeffects/events:2.useofmedication
forEPS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Analysis1.10.Comparison1BENZODIAZEPINESvsPLACEBO,Outcome10Adverseeffects/events:3.specific. 107
Analysis1.11.Comparison1BENZODIAZEPINESvsPLACEBO,Outcome11Leavingthestudyearly:1.anyreason. 107
Analysis2.1.Comparison2BENZODIAZEPINESvsANTIPSYCHOTICS,Outcome1Globalimpression: 1.no
improvement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
Analysis2.2.Comparison2BENZODIAZEPINESvsANTIPSYCHOTICS,Outcome2Globalimpression:2.needfor
additionalmedication. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Analysis 2.3. Comparison 2BENZODIAZEPINES vs ANTIPSYCHOTICS, Outcome 3 Global impression: 3.
sedation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
Analysis2.4.Comparison2BENZODIAZEPINESvsANTIPSYCHOTICS,Outcome4Globalimpression:4.average
change/endpointscore(CGI-S,high=worse). . . . . . . . . . . . . . . . . . . . . . . 111
Analysis2.5.Comparison2BENZODIAZEPINESvsANTIPSYCHOTICS,Outcome5Globalimpression:6.average
endpointscore(IMPS,high=worse). . . . . . . . . . . . . . . . . . . . . . . . . . 112
Analysis 2.6. Comparison 2 BENZODIAZEPINES vsANTIPSYCHOTICS, Outcome 6 Behaviour: 2. average
change/endpointscore(ABS,high=worse). . . . . . . . . . . . . . . . . . . . . . . . 112
Analysis2.7.Comparison2BENZODIAZEPINESvsANTIPSYCHOTICS,Outcome7Behaviour:4.averagechange
score(OAS,high=worse). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
Benzodiazepinesforpsychosis-inducedaggressionoragitation(Review) i
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Analysis2.8. Comparison 2BENZODIAZEPINESvsANTIPSYCHOTICS,Outcome8Mental state:1.average
change/endpointscore(BPRS,high=worse). . . . . . . . . . . . . . . . . . . . . . . . 114
Analysis2.9.Comparison2BENZODIAZEPINESvsANTIPSYCHOTICS,Outcome9Mentalstate:2.averageendpoint
score(BPRSpsychosissubscale,high=worse). . . . . . . . . . . . . . . . . . . . . . . 115
Analysis2.10.Comparison2BENZODIAZEPINESvsANTIPSYCHOTICS,Outcome10Mentalstate:3.average
changescore(PANSS,high=worse). . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Analysis2.11.Comparison2BENZODIAZEPINESvsANTIPSYCHOTICS,Outcome11Mentalstate:4.average
changescore(PANSS-excitedcomponent,high=worse). . . . . . . . . . . . . . . . . . . . 116
Analysis2.12.Comparison2BENZODIAZEPINESvsANTIPSYCHOTICS,Outcome12Adverseeffects/events:1.
extrapyramidalsymptoms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
Analysis2.13.Comparison2BENZODIAZEPINESvsANTIPSYCHOTICS,Outcome13Adverseeffects/events:2.use
ofmedicationforEPS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
Analysis2.14.Comparison2BENZODIAZEPINESvsANTIPSYCHOTICS,Outcome14Adverseeffects/events:3.
specific. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Analysis2.15.Comparison2BENZODIAZEPINESvsANTIPSYCHOTICS,Outcome15Leavingthestudyearly:1.
anyreason. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
Analysis3.1.Comparison3BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEBENZODIAZEPINES,Outcome
1Globalimpression:1.noimprovement. . . . . . . . . . . . . . . . . . . . . . . . . 121
Analysis3.2.Comparison3BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEBENZODIAZEPINES,Outcome
2Globalimpression:2.needforadditionalmedication. . . . . . . . . . . . . . . . . . . . 122
Analysis3.3.Comparison3BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEBENZODIAZEPINES,Outcome
3Globalimpression:3.sedation. . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Analysis3.4.Comparison3BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEBENZODIAZEPINES,Outcome
4Behaviour:1.averageendpointscore(ABS,high=worse). . . . . . . . . . . . . . . . . . . 124
Analysis3.5.Comparison3BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEBENZODIAZEPINES,Outcome
5Mentalstate:1.averageendpointscore(BPRS,high=worse). . . . . . . . . . . . . . . . . 124
Analysis3.7.Comparison3BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEBENZODIAZEPINES,Outcome
7Mentalstate:2.averageendpointscore(BPRSpsychosissubscale,high=worse). . . . . . . . . . . 125
Analysis3.8.Comparison3BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEBENZODIAZEPINES,Outcome
8Mentalstate:1.averageendpointscore(PANSS,high=worse). . . . . . . . . . . . . . . . . 126
Analysis3.10.Comparison3BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEBENZODIAZEPINES,Outcome
10Adverseeffects/events:1.extrapyramidalsymptoms. . . . . . . . . . . . . . . . . . . . 127
Analysis3.11.Comparison3BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEBENZODIAZEPINES,Outcome
11Adverseeffects/events:2.useofmedicationforEPS. . . . . . . . . . . . . . . . . . . . 127
Analysis3.12.Comparison3BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEBENZODIAZEPINES,Outcome
12Adverseeffects/events:3.specific. . . . . . . . . . . . . . . . . . . . . . . . . . . 128
Analysis3.13.Comparison3BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEBENZODIAZEPINES,Outcome
13Leavingthestudyearly:1.anyreason. . . . . . . . . . . . . . . . . . . . . . . . . 128
Analysis4.1.Comparison4BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEANTIPSYCHOTICS,Outcome1
Globalimpression:1.noimprovement. . . . . . . . . . . . . . . . . . . . . . . . . . 129
Analysis4.2.Comparison4BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEANTIPSYCHOTICS,Outcome2
Globalimpression:2.needforadditionalmedication. . . . . . . . . . . . . . . . . . . . . 130
Analysis4.3.Comparison4BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEANTIPSYCHOTICS,Outcome3
Globalimpression:3.needforadditionalmedication(meandose,high=worse). . . . . . . . . . . 130
Analysis4.4.Comparison4BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEANTIPSYCHOTICS,Outcome4
Globalimpression:4.sedation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Analysis4.5.Comparison4BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEANTIPSYCHOTICS,Outcome5
Globalimpression:5.averagechangescore(RSS,high=worse). . . . . . . . . . . . . . . . . 132
Analysis4.6.Comparison4BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEANTIPSYCHOTICS,Outcome6
Behaviour:1.averageendpointscore(ABS,high=worse). . . . . . . . . . . . . . . . . . . 132
Analysis4.7.Comparison4BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEANTIPSYCHOTICS,Outcome7
Behaviour:2.averageendpointscore(OAS,high=worse). . . . . . . . . . . . . . . . . . . 133
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Analysis4.8.Comparison4BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEANTIPSYCHOTICS,Outcome8
Behaviour:4.averageendpointscore(OASSagitationscale,high=worse). . . . . . . . . . . . . . 133
Analysis4.9.Comparison4BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEANTIPSYCHOTICS,Outcome9
Mentalstate:1.averageendpointscore(BPRS,high=worse). . . . . . . . . . . . . . . . . . 134
Analysis4.10.Comparison4BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEANTIPSYCHOTICS,Outcome
10Mentalstate:2.averageendpointscore(BPRSpsychosissubscale,high=worse). . . . . . . . . . 134
Analysis4.11.Comparison4BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEANTIPSYCHOTICS,Outcome
11Adverseeffects/events:1.extrapyramidalsymptoms. . . . . . . . . . . . . . . . . . . . 135
Analysis4.12.Comparison4BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEANTIPSYCHOTICS,Outcome
12Adverseeffects/events:2.useofmedicationforEPS. . . . . . . . . . . . . . . . . . . . 135
Analysis4.13.Comparison4BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEANTIPSYCHOTICS,Outcome
13Adverseeffects/events:3.specific. . . . . . . . . . . . . . . . . . . . . . . . . . . 136
Analysis4.14.Comparison4BENZODIAZEPINES+ANTIPSYCHOTICSvsSAMEANTIPSYCHOTICS,Outcome
14Hospitalandserviceoutcomes:1.changesinhospitalstatus. . . . . . . . . . . . . . . . . 137
Analysis5.1.Comparison5BENZODIAZEPINES+ANTIPSYCHOTICSvsDIFFERENTANTIPSYCHOTICS,
Outcome1Globalimpression:1.noimprovement. . . . . . . . . . . . . . . . . . . . . . 137
Analysis5.3.Comparison5BENZODIAZEPINES+ANTIPSYCHOTICSvsDIFFERENTANTIPSYCHOTICS,
Outcome3Globalimpression:3.sedation. . . . . . . . . . . . . . . . . . . . . . . . 138
Analysis5.4.Comparison5BENZODIAZEPINES+ANTIPSYCHOTICSvsDIFFERENTANTIPSYCHOTICS,
Outcome4Globalimpression:4.averageendpointscore(RSS,high=worse). . . . . . . . . . . . 139
Analysis5.5.Comparison5BENZODIAZEPINES+ANTIPSYCHOTICSvsDIFFERENTANTIPSYCHOTICS,
Outcome5Behaviour:1.averagechangescore(OAS,high=worse). . . . . . . . . . . . . . . . 140
Analysis5.6.Comparison5BENZODIAZEPINES+ANTIPSYCHOTICSvsDIFFERENTANTIPSYCHOTICS,
Outcome6Behaviour:2.averageendpointscore(OASSagitationscale,high=worse). . . . . . . . . 141
Analysis5.7.Comparison5BENZODIAZEPINES+ANTIPSYCHOTICSvsDIFFERENTANTIPSYCHOTICS,
Outcome7Mentalstate:1.averageendpointscore(PANSS,high=worse). . . . . . . . . . . . . 141
Analysis5.8.Comparison5BENZODIAZEPINES+ANTIPSYCHOTICSvsDIFFERENTANTIPSYCHOTICS,
Outcome8Mentalstate:2.averageendpointscore(PANSS-excitedcomponent,high=worse). . . . . . 142
Analysis5.9.Comparison5BENZODIAZEPINES+ANTIPSYCHOTICSvsDIFFERENTANTIPSYCHOTICS,
Outcome9Adverseeffects/events:1.sideeffects. . . . . . . . . . . . . . . . . . . . . . 143
Analysis5.10.Comparison5BENZODIAZEPINES+ANTIPSYCHOTICSvsDIFFERENTANTIPSYCHOTICS,
Outcome10Adverseeffects/events:2.extrapyramidalsymptoms. . . . . . . . . . . . . . . . . 144
Analysis5.11.Comparison5BENZODIAZEPINES+ANTIPSYCHOTICSvsDIFFERENTANTIPSYCHOTICS,
Outcome11Adverseeffects/events:3.specific. . . . . . . . . . . . . . . . . . . . . . . 144
Analysis 6.1. Comparison 6 BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS +
ANTIPSYCHOTICS,Outcome1Behaviour:3.averageendpointscore(OAS,high=worse). . . . . . . 145
Analysis 6.2. Comparison 6 BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS +
ANTIPSYCHOTICS,Outcome2Leavingthestudyearly:1.anyreason. . . . . . . . . . . . . . 145
Analysis7.1.Comparison7BENZODIAZEPINESvsANTIPSYCHOTICS+ANTIHISTAMINES,Outcome1Global
impression:1.noimprovement. . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
Analysis7.2.Comparison7BENZODIAZEPINESvsANTIPSYCHOTICS+ANTIHISTAMINES,Outcome2Global
impression:2.needforadditionalmedication. . . . . . . . . . . . . . . . . . . . . . . 146
Analysis7.3.Comparison7BENZODIAZEPINESvsANTIPSYCHOTICS+ANTIHISTAMINES,Outcome3Global
impression:3.sedation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Analysis7.4.Comparison7BENZODIAZEPINESvsANTIPSYCHOTICS+ANTIHISTAMINES,Outcome4Global
impression:4.averageendpointscore(CGI,high=worse). . . . . . . . . . . . . . . . . . . 148
Analysis7.5.Comparison7BENZODIAZEPINESvsANTIPSYCHOTICS+ANTIHISTAMINES,Outcome5Adverse
effects/events:1.specific. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Analysis7.6.Comparison7BENZODIAZEPINESvsANTIPSYCHOTICS+ANTIHISTAMINES,Outcome6Leaving
thestudyearly:1.anyreason. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
Analysis7.7.Comparison7BENZODIAZEPINESvsANTIPSYCHOTICS+ANTIHISTAMINES,Outcome7Hospital
andserviceoutcomes:1.changesinhospitalstatus. . . . . . . . . . . . . . . . . . . . . . 150
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Analysis 8.1. Comparison 8 BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS +
ANTIHISTAMINES,Outcome1Globalimpression:1.noimprovement. . . . . . . . . . . . . . 151
Analysis 8.2. Comparison 8 BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS +
ANTIHISTAMINES, Outcome2Globalimpression: 2.needfor additional medication (meandose, high=
worse). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
Analysis 8.3. Comparison 8 BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS +
ANTIHISTAMINES,Outcome3Globalimpression:3.sedation. . . . . . . . . . . . . . . . . 152
Analysis 8.4. Comparison 8 BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS +
ANTIHISTAMINES,Outcome4Globalimpression:4.averagechangescore(RSS,high=worse). . . . . 152
Analysis 8.5. Comparison 8 BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS +
ANTIHISTAMINES,Outcome5Behaviour:1.averageendpointscore(OAS,high=worse). . . . . . . 153
Analysis 8.6. Comparison 8 BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS +
ANTIHISTAMINES,Outcome6Behaviour:2.averageendpointscore(OASSagitationscale,high=worse). 153
Analysis 8.7. Comparison 8 BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS +
ANTIHISTAMINES,Outcome7Adverseeffects/events:1.extrapyramidalsymptoms. . . . . . . . . 154
Analysis 8.8. Comparison 8 BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS +
ANTIHISTAMINES,Outcome8Adverseeffects/events:2.specific. . . . . . . . . . . . . . . . 154
Analysis9.1.Comparison9SENSITIVITYANALYSIS:BENZODIAZEPINESvsANTIPSYCHOTICS-1.Random
sequencegeneration,Outcome1Globalimpression:1.noimprovement. . . . . . . . . . . . . . 155
Analysis9.2.Comparison9SENSITIVITYANALYSIS:BENZODIAZEPINESvsANTIPSYCHOTICS-1.Random
sequencegeneration,Outcome2Globalimpression:2.sedation. . . . . . . . . . . . . . . . . 156
Analysis9.3.Comparison9SENSITIVITYANALYSIS:BENZODIAZEPINESvsANTIPSYCHOTICS-1.Random
sequencegeneration,Outcome3Adverseeffects/events:1.extrapyramidalsymptoms. . . . . . . . . . 157
Analysis10.1.Comparison10SENSITIVITYANALYSIS:BENZODIAZEPINESvsANTIPSYCHOTICS-2.Allocation
concealment,Outcome1Globalimpression:1.noimprovement. . . . . . . . . . . . . . . . . 158
Analysis10.2.Comparison10SENSITIVITYANALYSIS:BENZODIAZEPINESvsANTIPSYCHOTICS-2.Allocation
concealment,Outcome2Globalimpression:2.sedation. . . . . . . . . . . . . . . . . . . . 159
Analysis10.3.Comparison10SENSITIVITYANALYSIS:BENZODIAZEPINESvsANTIPSYCHOTICS-2.Allocation
concealment,Outcome3Adverseeffects/events:1.extrapyramidalsymptoms. . . . . . . . . . . . 160
Analysis11.1.Comparison11SENSITIVITYANALYSIS:BENZODIAZEPINESvsANTIPSYCHOTICS-3.Blinded
outcomemeasurement,Outcome1Globalimpression:1.noimprovement. . . . . . . . . . . . . 161
Analysis11.2.Comparison11SENSITIVITYANALYSIS:BENZODIAZEPINESvsANTIPSYCHOTICS-3.Blinded
outcomemeasurement,Outcome2Globalimpression:2.sedation. . . . . . . . . . . . . . . . 162
Analysis11.3.Comparison11SENSITIVITYANALYSIS:BENZODIAZEPINESvsANTIPSYCHOTICS-3.Blinded
outcomemeasurement,Outcome3Adverseeffects/events:1.extrapyramidalsymptoms. . . . . . . . . 163
Analysis12.1. Comparison 12 SENSITIVITYANALYSIS:BENZODIAZEPINES vsANTIPSYCHOTICS -4.
Incompleteoutcomedata(attritionbias),Outcome1Globalimpression:1.noimprovement. . . . . . . 164
Analysis12.2. Comparison 12 SENSITIVITYANALYSIS:BENZODIAZEPINES vsANTIPSYCHOTICS -4.
Incompleteoutcomedata(attritionbias),Outcome2Globalimpression:2.sedation. . . . . . . . . . 165
Analysis12.3. Comparison 12 SENSITIVITYANALYSIS:BENZODIAZEPINES vsANTIPSYCHOTICS -4.
Incompleteoutcomedata(attritionbias),Outcome3Adverseeffects/events:1.extrapyramidalsymptoms. . . 166
ADDITIONALTABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
WHAT’SNEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
CONTRIBUTIONSOFAUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
DECLARATIONSOFINTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
SOURCESOFSUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
DIFFERENCESBETWEENPROTOCOLANDREVIEW . . . . . . . . . . . . . . . . . . . . . 183
INDEXTERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
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[InterventionReview]
Benzodiazepines for psychosis-induced aggression or agitation
DonnaGillies1,StephanieSampson2,AlisonBeck3,JohnRathbone4
1WesternSydneyandNepeanBlueMountainsLocalHealthDistricts-MentalHealth,Parramatta,Australia.2CochraneSchizophrenia
Group,TheUniversityofNottingham,Nottingham,UK.3TrustHQ,SouthLondonandMaudsleyNHSFoundationTrust,London,
UK.4HEDS,ScHARR,TheUniversityofSheffield,Sheffield,UK
Contactaddress:DonnaGillies,WesternSydneyandNepeanBlueMountainsLocalHealthDistricts-MentalHealth,Cumberland
Hospital,LockedBag7118,Parramatta,NSW,2150,[email protected].
Editorialgroup:CochraneSchizophreniaGroup.
Publicationstatusanddate:Newsearchforstudiesandcontentupdated(conclusionschanged),publishedinIssue9,2013.
Reviewcontentassessedasup-to-date: 1June2012.
Citation: GilliesD,SampsonS,BeckA,RathboneJ.Benzodiazepinesforpsychosis-inducedaggressionoragitation.CochraneDatabase
ofSystematicReviews2013,Issue9.Art.No.:CD003079.DOI:10.1002/14651858.CD003079.pub4.
Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
ABSTRACT
Background
Acutepsychoticillness,especiallywhenassociatedwithagitatedorviolentbehaviour,canrequireurgentpharmacologicaltranquillisation
or sedation. In several countries, clinicians oftenuse benzodiazepines (eitheralone or in combination with antipsychotics) for this
outcome.
Objectives
Toestimatetheeffectsofbenzodiazepines,aloneorincombinationwithantipsychotics,whencomparedwithplaceboorantipsychotics,
aloneorincombinationwithantihistamines,tocontroldisturbedbehaviourandreducepsychoticsymptoms.
Searchmethods
WesearchedtheCochraneSchizophreniaGroup’sregister(January2012),inspectedreferencelistsofincludedandexcludedstudies
andcontactedauthorsofrelevantstudies.
Selectioncriteria
Weincludedallrandomisedclinicaltrials(RCTs)comparingbenzodiazepinesaloneorincombinationwithanyantipsychotics,versus
antipsychoticsaloneorincombinationwithanyotherantipsychotics,benzodiazepinesorantihistamines,forpeoplewithacutepsychotic
illnesses.
Datacollectionandanalysis
Wereliablyselectedstudies,qualityassessedthemandextracteddata.Forbinaryoutcomes,wecalculatedstandardestimatesofrelative
risk (RR) and their 95% confidence intervals (CI) using a fixed-effect model. For continuous outcomes, we calculated the mean
difference(MD)betweengroups.Ifheterogeneitywasidentified,thiswasexploredusingarandom-effectsmodel.
Mainresults
Weincluded21trialswithatotalofn=1968 participants. Therewasnosignificant differenceformostoutcomesintheonetrial
thatcomparedbenzodiazepineswithplacebo,althoughtherewasahigherriskofnoimprovementinpeoplereceivingplacebointhe
mediumterm(oneto48hours)(n=102,1RCT,RR0.62,95%CI0.40to0.97,verylowqualityevidence).
Benzodiazepinesforpsychosis-inducedaggressionoragitation(Review) 1
Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Therewasnodifferenceinthenumberofparticipantswhohadnotimprovedinthemediumtermwhenbenzodiazepineswerecompared
withantipsychotics(n=308,5RCTs,RR1.10,95%CI0.85to1.42,lowqualityevidence);however,peoplereceivingbenzodiazepines
werelesslikelytoexperienceextrapyramidaleffects(EPS)inthemediumterm(n=536, 8RCTs, RR0.15,95%CI0.06to0.39,
moderatequalityofevidence).Datacomparingcombinedbenzodiazepinesandantipsychoticsversusbenzodiazepinesalonedidnotyield
anysignificantresults.
When comparing combined benzodiazepines/antipsychotics (all studies compared haloperidol) with the same antipsychotics alone
(haloperidol),therewas no differencebetweengroups inimprovementinthemediumterm(n=155, 3RCTs, RR 1.27, 95% CI
0.94 to 1.70, verylow quality evidence)but sedation was more likelyinpeople who receivedthe combination therapy(n =172, 3
RCTs,RR1.75,95%CI1.14to2.67,verylowqualityevidence).However,moreparticipantsreceivingcombinedbenzodiazepinesand
haloperidolhadnotimprovedbymediumtermwhencomparedtoparticipantsreceivingolanzapine(n=60,1RCT,RR25.00,95%
CI1.55to403.99,verylowqualityevidence)orziprasidone(n=60,1RCT,RR4.00,95%CI1.25to12.75verylowqualityevidence).
Whenhaloperidolandmidazolamwerecomparedwitholanzapine,therewassomeevidencethecombinationwassuperiorintermsof
improvement,sedationandbehaviour.
Authors’conclusions
Theevidencefromtrialsfortheuseofbenzodiazepinesaloneisnotgood.Therewererelativelylittlegooddataandmosttrialsaretoo
smalltohighlightdifferencesineitherpositiveornegativeeffects.Addingabenzodiazepinetootherdrugsdoesnotseemtoconferclear
advantageandhaspotentialforaddingunnecessaryadverseeffects.Soleuseofolderantipsychoticsunaccompaniedbyanticholinergic
drugsseemsdifficulttojustify.Muchmorehighqualityresearchisneededinthisarea.
PLAIN LANGUAGE SUMMARY
Benzodiazepinesaloneorincombinationwithantipsychoticdrugsforacutepsychosis
Peoplewithmentalhealthproblemsmayexhibitagitated,violentandaggressivebehaviourwhichcanbeadangertothemselvesorothers.
Usually,de-escalationtechniquessuchastalkingtothepatientareusedtocalmdownthesituation.However,people’sbehaviourmay
betoodisturbed,violentoragitated.Inthesecircumstances,rapidtranquillisationisgiventoachieveastateofcalm.Threemajorclasses
ofdrugsareusedtoachieverapidtranquillisation:typicalantipsychotics;benzodiazepines;andmorerecentlyatypicalantipsychotics.
Thereviewincluded21studies involving 1968 people.Theaimwastoexplorethetranquillising effectsof benzodiazepines (alone
orincombinationwithantipsychotics;placebo;andantihistamines).Overall,thereisinsufficientinformationinthese21studiesto
supportor refute theuse of benzodiazepines (alone or incombination with otherdrugs, whereemergencydrugs are needed).The
majorityofstudiesaretoosmall,sothatlargerandmoreinformativestudiesarerequiredbeforedefiniteconclusionscanbedrawnas
totheeffectivenessofbenzodiazepines.However,therewasgoodevidencetosuggestthatbenzodiazepinesareatleastaseffectiveas
antipsychoticsinreducingtheagitationassociatedwithmentalillness.Sideeffectssuchasweightgain,shaking,tremorsandslurred
speechweresignificantlyhigherinpeoplewhoreceivedantipsychotics.Therefore,ifantipsychoticsareusedforrapidtranquillisation,
theyshouldbegivenwithothercalmingdrugs(anticholinergicmedication)whichcanpreventsideeffects.Therewasalsosomeevidence
thatthecombinationofbenzodiazepineswithantipsychoticswassuperiortoeitherdrugaloneandmayalsoreducesideeffects.
In summary, there is no strong information from these studies to support or refute the use of benzodiazepines (with or without
antipsychoticsorincombinationwithotherdrugs)ifthesituationhasdeterioratedtosuchanextentthatemergencydrugsareneeded.
However,the lower ratesof side effectsinpeople receiving benzodiazepines may be areason to choose benzodiazepines over older
antipsychotics. Lackofgoodqualityevidenceleavesmanagers,clinicians, psychiatristsandpolicymakerswithdifficultdecisionsto
make.Thereiscurrentlylimitedevidencetosuggestthatbenzodiazepines(aloneorincombination withantipsychotics) areclearly
superiortoantipsychotics(aloneorincombinationwithantihistamines)inreducingacutepsychoticbehaviour,suchasaggressionor
agitation.
ThissummaryhasbeenwrittenbyBenjaminGray,ServiceUserandServiceUserExpert,RethinkMentalIllness.
Benzodiazepinesforpsychosis-inducedaggressionoragitation(Review) 2
Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
CoeB SUMMARY OF FINDINGS FOR THE MAIN COMPARISON [Explanation]
pn
yrzo
ighdia
tz
©ep
2013ines BENZODIAZEPINEScomparedtoPLACEBOforpsychosis-inducedaggressionoragitation
Tfo
hr
eCpsy Patientorpopulation:patientswithpsychosis-inducedaggressionoragitation
ochrachosis SInetettrinvegns:tihoons:pBiEtaNlsZO(RDoIAmZaEnPiaIN&ESUS)
neCo-induc Comparison:PLACEBO
llaed
boratioaggres Outcomes Illustrativecomparativerisks*(95%CI) R(9e5la%tivCeI)effect N(sotuodfiePsa)rticipants Q(GuRaAlitDyEo)ftheevidence Comments
n.sio
Publisnora Assumedrisk Correspondingrisk
hg
edita PLACEBO BENZODIAZEPINES
bytio
John(R Global impression - no 569per10001 353per1000 RR0.62 102 ⊕(cid:13)(cid:13)(cid:13)
ne
Wvie improvement - medium (227to552) (0.4to0.97) (1study) verylow2,3,4,5
ileyw) term
& Asdefinedineachstudy
S
on Follow-up:24hours
s
,
L
td. Globalimpression-need 529per10001 529per1000 RR1 102 ⊕(cid:13)(cid:13)(cid:13)
for additional medica- (365to762) (0.69to1.44) (1study) verylow2,3,4,5
tion-mediumterm
Number of participants
requiringadditionalmedi-
cation
Follow-up:24hours
Global impression - se- 59per10001 98per1000 RR1.67 102 ⊕(cid:13)(cid:13)(cid:13)
dation-mediumterm (25to389) (0.42to6.61) (1study) verylow2,3,4,5
Number of participants
sedated
Follow-up:24hours
3
CB
oe
pn
yrzo
ighdia
t©zep Adverse effects/events 59per10001 19per1000 RR0.33 102 ⊕(cid:13)(cid:13)(cid:13)
2013Tinesfo -tomexstr-apmyerdaimumidatlersmymp- (2to182) (0.04to3.1) (1study) verylow2,3,4,5
herp Number of instances
Cochrasychosis otofmesxtrapyramidal symp-
ne-in Follow-up:24hours
Coduc
llaboratioedaggres Smaetnistf-acgteionnerawlith treat- Seecomment Seecomment Notestimable 0(0) Seecomment Nouotcosmtude.y reported this
n.sio
Publisnora Ecocsotn-oemffeicctivoeuntecossmes - Seecomment Seecomment Notestimable 0(0) Seecomment Nouotcosmtude.y reported this
hg
edita
bytio *Thebasisfor the assumedrisk(e.g.themediancontrol groupriskacross studies) isprovidedinfootnotes. Thecorresponding risk(andits95%confidence interval) isbasedonthe
John(R assumedriskinthecomparisongroupandtherelativeeffectoftheintervention(andits95%CI).
ne
Wvie CI:Confidenceinterval;RR:Riskratio;
ileyw)
& GRADEWorkingGroupgradesofevidence
S
on Highquality:Furtherresearchisveryunlikelytochangeourconfidenceintheestimateofeffect.
s
,L Moderatequality:Furtherresearchislikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandmaychangetheestimate.
td
. Lowquality:Furtherresearchisverylikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandislikelytochangetheestimate.
Verylowquality:Weareveryuncertainabouttheestimate.
1Assumedrisk:meanbaselineriskpresentedforsinglestudy.Equateswiththatofcontrolgroup.
2Riskofbias:’veryserious’-90%oftrialauthorsandco-authorswereemployedbytrialsponsorsatthetimeofthestudy.
3Riskofbias:’serious’-randomisationpoorlydescribed.
4 Indirectness: ’serious’-onlyonestudyreportedresultsonthisoutcome. Therewasanadditional treatmentarm,thereforethetotal
amountofparticipantsinthestudyarenotaccountedfor.
5Imprecision:’serious’-onlyonestudyreporteddataforthisoutcome.
4
BACKGROUND aggression, but itis not clear just how effectiveand, if they are
betterorworsethanothercompoundsorcombinationsofcom-
pounds.
Descriptionofthecondition
Acutelypsychoticpeoplemayexhibitagitatedandaggressivebe-
haviour which can presenta danger to themselvesor others. In Whyitisimportanttodothisreview
ordertoensureasafeandtherapeuticenvironment,de-escalation
Guidancesuggestsbenzodiazepinesareatleastaseffectiveasan-
techniquesshouldbeusedtocalmthepatient(NICE2005;Rocca
tipsychoticsincontrollingseverelyagitatedbehaviour(Allen2000;
2006).Frequently,however,thebehaviourmaybetoodisturbed
NICE2005;Rocca2006,)andindeedthiswasthefindingofthe
oragitatedforthesemethodstobeeffective,anditmightprove
original Cochrane review (Gillies 2005). Some authors suggest
imperativethatfurtheractionintheformofrapidtranquillisation
thatthecombinationofantipsychoticswithbenzodiazepinesmay
isgiven(NICE2005;Rocca2006).Theaimofrapidtranquilli-
bemoreadvantageousthaneitherdrugalone(NICE2005;Rocca
sationistoachieveastateofcalmwhichissufficienttominimise
2006)but therewas inadequate evidence of this in theoriginal
riskofharmtotheagitatedpersonthemselves,ortoothersaround
Cochranereview(Gillies2005).Thisupdateincludesallnewtri-
them,andallowtreatmentoftheunderlyingcondition(Battaglia
alscomparingbenzodiazepines(aloneorcombinedwithantipsy-
2005;NICE2005).Rapidtranquillisationmayserveasprimary
chotics)withantipsychotics(aloneorincombination withben-
therapy in such instances but may also be used in conjunction
zodiazepines).Inaddition,inthisupdate,weincludedtrialsthat
withotherde-escalationmethods(Marder2006;NICE2005).
comparedbenzodiazepinesaloneorincombinationwithantipsy-
chotics,comparedtootherantipsychotics,benzodiazepinesoran-
tihistamines.
Descriptionoftheintervention
While thereis evidence thatboth benzodiazepines and antipsy-
Rapid tranquillisation is commonly used in emergency settings choticsareeffectiveindecreasingagitation,bothcancauseunde-
ingeneralandpsychiatrichospitalsaroundtheworld(Goedhard sirableadverseeffects.Acutephasetreatmentwiththetypicalan-
2006; Marder 2006). Three major classes of drugs are used to tipsychoticdrugsmayresultindebilitatingextrapyramidalsymp-
achieve rapidtranquillisation: the typical antipsychotics; benzo- toms (EPS) including Parkinson’s-like symptoms, hypotension,
diazepines; and more recently, atypical antipsychotics (Marder lowering of the seizure threshold, cardiac arrhythmia, and neu-
2006).Intramuscularinjectionsoftypicalantipsychoticsandben- rolepticmalignantsyndrome(Battaglia2005;NICE2005;Rocca
zodiazepines, alone orincombination, havebeenthetreatment 2006).BenzodiazepinesproduceEPSlessfrequently,butcancause
ofchoiceforseveraldecades.Inareviewoftheresearchliterature respiratorydepression,ataxia,excessivesedation,memoryimpair-
(Battaglia 2005), thetypical antipsychotic, haloperidol,and the mentandparadoxicaldisinhibition(Battaglia2005;Marder2006;
benzodiazepine,lorazepam,werereportedasthemostwidelyused Rocca2006).Theadverseeffectprofileofcombinedtherapywith
drugs.However,thedrugsusedforrapidtranquillisationmayvary benzodiazepinesandantipsychoticsisasyetunclear(Gillies2005)
widelyindifferentcountries.AsurveyinRiodeJaneiro,Brazil, althoughithasbeensuggestedthatthecombinationtherapymay
showedthatahaloperidol-promethazinemixturewascommonly decrease the incidence of side effects(Battaglia 2005). It isalso
used(Huf2002)whileasurveyofAfricanpsychiatristsfoundthat thoughtthatthebroaderactivityprofileofatypicalantipsychotics
chlorpromazineanddiazepamweremostcommonlyprescribed, maymeantheyarelesslikelytoproducetheEPSsideeffectsofthe
althoughthechoiceofdrugtendedtobegovernedbyavailabil- typicalantipsychotics(Duggan2005;Essali2009;Silveira2002)
ity rather than preference (James 2011). With the introduction buttherehavebeenreportsofsevereadverseeventsassociatedwith
of parenteral forms of theatypical antipsychotics, theseare also theintramuscularadministrationofthesedrugs(Battaglia2005).
gaininginpopularityasthefirst-linetreatmentforagitationinthe Thisisoneofaseriesofsimilarreviews(Table3).
psychiatricemergencysetting(Marder2006;Mintzer2006).
The benzodiazepine family islarge (Table 1)and with different
characteristicsofmetabolism(Table2).
OBJECTIVES
Howtheinterventionmightwork Toestimatetheeffectsofbenzodiazepinesusedaloneorincombi-
nationwithantipsychoticdrugsforacutelydisturbedpeoplewith
Amongotheractions, benzodiazepinesenhancetheeffectofthe
psychosis-inducedaggressionoragitation.
inhibitoryneurotransmittergamma-aminobutyric acid(GABA),
whichresultsinsleepinducing,sedative,anti-anxiety,musclere-
laxantandamnesiceffects.Firstdiscoveredin1955,throughlong
experience,itisclearthatthesedrugsareeffectiveformanaging METHODS
Benzodiazepinesforpsychosis-inducedaggressionoragitation(Review) 5
Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.