Antipsychotics for Mania

Mary Butler; Snezana Urosevic; Priyanka Desai; Scott R. Sponheim; Jonah Popp; Victoria A. Nelson; Viengneesee Thao; Benjamin Sunderlin

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Butler M, Urosevic S, Desai P, et al. Treatment for Bipolar Disorder in Adults: A Systematic Review [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2018 Aug. (Comparative Effectiveness Review, No. 208.)

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Treatment for Bipolar Disorder in Adults: A Systematic Review [Internet].

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Appendix EAntipsychotics for Mania

Section 1. Aripiprazole for Acute Mania

Appendix Table E1Characteristics of eligible studies: aripiprazole for acute mania

Study, Year Design Location Funder Risk of Bias PMID	# Randomized Age (mean) Sex (% Female) Race (% White) Diagnosis (% BP-I, II, NOS) Setting	Inclusions Key Exclusions	Intervention Dosage	Comparison Dosage	Follow-up Duration	Outcomes Reported Withdrawal (%) at endpoint
Kanba, 20141 RCT Multisite Asia Industry RoB High 22540407	N = 258 Mean Age 38 Female 59% Japanese 32% Korean/Chinese 43% Other 25% BP-I 100% Inpatient	Manic/Mixed episode; YMRS ≥ 20; Current episode <4 weeks First Manic Episode Schizoaffective Neurological Disorders Other Mental Health Substance Abuse Pregnant/Nursing	Aripiprazole 24 mg/day (22.9 mg/day)	Placebo	3 weeks	YMRS CGI-BP-S Response Adverse Events Withdrawal 47%
Young, 20092 RCT Multisite All Continents Industry RoB Moderate 19118324	N = 332 Mean Age 41 Female 57% White 78% BP-I 100% Inpatient (weeks 1–2) Outpatient (weeks 3–12)	Manic/Mixed in acute relapse; YMRS ≥ 20 and MADRS ≤ 17 at baseline, < 25% decrease in YMRS score and ≤4 point MADRS score between screening and baseline visits; Current episode < 3 weeks First Manic Episode Schizoaffective Neurological Disorders Other Mental Health Taking Other Meds Substance Abuse	Aripiprazole 15–30 mg/day (22.0 mg/day)	C1: Placebo C2: Haloperidol 5–15 mg/day (7.4 mg/day)	12 weeks for aripiprazole and haloperidol; 3 weeks for placebo	YMRS CGI-BP-S Response Adverse Events EPS Withdrawal 27% at 3 weeks
Sachs, 20063 RCT Multisite North America Industry RoB High 16401666	N = 272 Mean Age 39 Female 51% White 72% BP-I 100% Inpatient (weeks 1–2) Outpatient (week 3)	Manic/Mixed episode; YMRS ≥ 20; Current episode < 4 weeks First Manic Episode Schizoaffective Substance Abuse Neurological Disorders Taking Other Meds Pregnant/Nursing Labs/Other Conditions	Aripiprazole 15–30 mg/day (27.7 mg/day)	Placebo	3 weeks	YMRS CGI-BP-S Response Adverse Events EPS Withdrawal 47%
Vieta, 20054 RCT Multisite Not Disclosed Industry RoB Moderate 16135860	N = 347 Mean Age 42 Female 28% Race NR BP-I 100% Inpatient or Outpatient	Manic/Mixed; YMRS ≥ 20; Current episode < 4 weeks Other Mental Health Taking Other Meds Substance Abuse	Aripiprazole 15–30 mg/day	C1: Placebo C2: Haloperidol 10–15 mg/day	3 weeks (with withdrawal < 50%; 12 weeks total)	YMRS CGI-BP-S Response Adverse Events EPS Withdrawal 34%

: Abbreviations: AIMS=Abnormal Involuntary Movement Scale; BARS=Barnes Akathisia Scale; BAS=Behavioral Approach System; BMI=Body Mass Index; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; C=comparison; CGI= Clinical Global Impressions; CGI-I=Clinical Global Impressions-Improvement; CGI-S =CGI-Severity; CGI-BP=Clinical Global Impressions Scale-Bipolar; CGI-BP-C= Clinical Global Impressions, Bipolar, Change Scale; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; C-SSRS=Columbia Suicide Severity Rating Scale; DAI-10=Drug Attitutde Inventory, 10 question version; DIEPSS=Drug-Induced Extra-Pyramidal Symptoms Scale; DSM=Diagnostic and Statistical Manual of Mental Disorders; EPS=extrapyramidal symptoms; ER=Extended Release; ESRS=Extrapyramidal Symptom Rating Scale; GAF=General Assessment of Functioning Scale; GAS=Global Assessment Scale; HAM-A=Hamilton Scale for Anxiety; HAM-D=Hamilton Scale for Depression; HRQL=Health-related quality of life; HRQOL=Health-related quality of life; I=intervention; IDS=Inventory for Depressive Symptoms; LIFE= Longitudinal Interval Follow-up Evaluation; MADRS=Montgomery-Asberg Depression Rating Scale; MAS=Bech-Rafaelsen Mania Rating Scale; MRS=Mania Rating Scale; MSRS=Manic state rating scale; NOS=not otherwise specified; NR=not reported; PANSS=Positive and Negative Syndrome Scale; PRS=Polygenic Risk Scores; PGWB=Psychological General Well-Being Index; PMID=PubMed Identification Number; PRS=Polygenic Risk Scores; Q-LES-Q=Quality of Life Enjoyment and Satisfaction Questionnaire; RCT=randomized controlled trial; ROB=risk of bias; SADS-C= Schedule for Affective Disorders and Schizophrenia-Change version; SAE=Serious Adverse Events; SAS=Simpson Angus Scale; SF-12=12-Item Short Form Health Survey; SF-36=36-Item Short Form Health Survey; SLICE=Streamlined Longitudinal Interview Clinical Evaluation; T=Trial; YMRS = Young Mania Rating Scale

Appendix Table E2Summary risk of bias assessments: aripiprazole for acute mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Aripiprazole	Kanba, 2014¹ Industry 22540407	High	High dropout rate (47% overall); Randomization and blinding procedures not disclosed.
	Young, 2009² Industry 19118324	High	Moderate dropout rate (28%); Randomization and blinding procedures not disclosed.
	Sachs, 2006⁵ Industry 16401666	High	High withdrawal rate (47%), randomization and blinding procedures not disclosed
	Vieta, 2005⁶ Industry 16135860	Moderate	Blinding not described, moderate dropout level (34%), not balanced between the groups. Groups may not be comparable at time of analysis.

: Abbreviations: ITT=Intention to Treat; PMID=PubMed Identification Number; LOCF=last observation carried forward

Aripirazole Forest Plots

Outcomes in studies assessed as having a high risk of bias, or low to moderate risk of bias but at least 40 percent attrition, are presented in grey tones. Both fixed-effect models and random-effects models are presented. We calculated fixed-effect models to provide a charitable estimate of the average effect among completed trials. However, we base our main conclusions on the random-effects models.

Appendix Figure E1Aripiprazole vs. placebo – response

Appendix Figure E2Aripiprazole vs. placebo – YMRS

Appendix Figure E3Aripiprazole vs. placebo – CGI-BP-S

Appendix Figure E4Aripiprazole vs. placebo – withdrawal lack of efficacy

Appendix Figure E5Aripiprazole vs. placebo – withdrawal adverse events

Appendix Figure E6Aripiprazole vs. placebo – overall withdrawal

Appendix Figure E7Aripiprazole vs. placebo – harms - akasthesia

Appendix Figure E8Aripiprazole vs. placebo – harms – emergent depression

Appendix Figure E9Aripiprazole vs. placebo – harms – emergent manic episode

Appendix Figure E10Aripiprazole vs. placebo – harms – serious adverse event

Appendix Figure E11Aripiprazole vs. placebo – harms – weight gain

Appendix Figure E12Aripiprazole vs. haloperidol – response

Appendix Figure E13Aripiprazole vs. haloperidol – remission

Appendix Figure E14Aripiprazole vs. haloperidol – withdrawal – adverse events

Appendix Figure E15Aripiprazole vs. haloperidol – withdrawal – overall

Appendix Figure E16Aripiprazole vs. haloperidol – harms – akathisia

Appendix Figure E17Aripiprazole vs. haloperidol – harms – emergent depression

Appendix Figure E18Aripiprazole vs. haloperidol – harms – extrapyramidal symptoms

Appendix Figure E19Aripiprazole vs. haloperidol – harms – serious adverse events

Appendix Table E3Outcomes summary: aripirazole versus placebo for acute mania

Drug	Study PMID RoB	Responder/Remitter	Symptom	Function	Other	AE
Aripiprazole	Kanba, 2014¹ 22540407 Moderate	See forest plot E1 above for Response.	See forest plot E2 above for YMRS.	NR	See forest plots E4, E5, E6 above for Withdrawals.	See forest plots E7, E8, E9, E10, E11 above for Adverse Effects. Very Serious AE 3 weeks 1 death during trial, unrelated to study medication
	Young, 2009² 19118324 Moderate	Remission 3 weeks NS Aripiprazole = 73/166 Placebo=56/152 OR = 1.35 (95% CI 0.86, 2.11) p 0.20	See forest plot E2 above for YMRS.	NR	See forest plots E4, E5, E6 above for Withdrawals.	See forest plots E7, E8, E9, E10, E11 above for Adverse Effects. Very Serious AE 3 weeks 1 non-fatal suicide attempt, unclear which study arm SAE 3 weeks Aripoprazole=19/166 Placebo=NR No statistical test reported Extrapyramidal Symptoms 3 weeks Aripoprazole=39/166 Placebo=NR No statistical test reported
	Sachs. 2006⁵ 16401666 Moderate	See forest plot E1 above for response.	See forest plot E2 above for YMRS.	NR	See forest plots E4, E5, E6 above for Withdrawals.	See forest plots E7, E8, E9, E10, E11 above for Adverse Effects.

: Abbreviations: AE=Adverse Events; ANCOVA=Analysis of Covariance; CGI=Clinical Global Impressions Scale; CI=Confidence Interval; EPS=extrapyramidal symptoms; ESRS=Extrapyrimidal Symptom Rating Scale; GAS=Global Assessment Scale; MADRS=Montgomery-Asberg Depression Rating Scale; NR=Not reported; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; ROB=Risk of Bias; SAE=Serious Adverse Events; YMRS = Young Mania Rating Scale

Appendix Table E4Strength of evidence assessment: aripiprazole versus placebo for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Aripiprazole vs. placebo	Response 3 wks YMRS 3 wks CGI-BP-S 3 wks Overall withdrawal Withdrawal lack of efficacy Withdrawal adverse events	3 RCT (n=823)	See forest plots	High	Consistent	Direct	Imprecise	Insufficient

: Abbreviations: CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; NS=not significant; RCT=randomized controlled trial; YMRS = Young Mania Rating Scale
: Notes:
1: Publication bias for antipsychotics, antidepressants, and behavioral interventions for depressive disorders is suspected.
2: Data were generally imprecise due to missing data from high attrition rates, which was commonly dealt with by Last Observation Carried Forward (LOCF). LOCF requires an assumption that the health status of patients who dropped out of the trial would not have changed had future observations been recorded, a strong assumption in the context of bipolar disorder research.

Appendix Table E5Outcomes summary: aripiprazole versus active comparator for acute mania

Comparison	Study PMID RoB	Responder/Remitter	Symptom	Function	Other	AE
Aripiprazole (15 or 30 mg/day) vs.. Haliperidol (5–15 mg/day)	Young, 2009² 19118324 Moderate High (12 weeks)	See forest plot above.	YMRS, Mean Change 3 weeks NS Aripiprazole =−12.0 Haloperidol =−12.8 No statistical test reported 12 weeks NS Aripiprazole =−17.2 Haloperidol =−17.8 No statistical test reported CGI-BP-Sev, Mean Change 3 weeks NS Aripiprazole =−1.4 Haloperidol =−1.5 No statistical test reported 12 weeks NS Aripiprazole =−2.1 Haloperidol =−2.2 No statistical test reported	NR	Overall Withdrawal 12 weeks NS Aripiprazole=72/167 Haloperidol=70/165 OR = 1.03 (95% CI 0.67, 1.59) ; P = 0.90 Withdrawal Due to Lack of Efficacy 3 weeks NS Aripiprazole=9/167 Haloperidol=10/165 OR = 0.88 (95% CI 0.35, 2.23) p= 0.79 12 weeks NS Aripiprazole=13/167 Haloperidol=11/165 OR = 1.18 (.51, 2.72) ; P = .694 Withdrawal Due to AEs 12 weeks NS Aripiprazole=24/167 Haloperidol=18/165 OR=1.37 (.71, 2.63) ; P = 0.34	Very Serious AEs 12 weeks 1 patient in haloperidol group suffered liver damage, potentially attributable to haloperidol Normalized Weight Change (>7% change) 12 weeks NS Aripiprazole= 5.1% Haloperidol= 5.8% OR = 0.87 No statistical test reported Cases of Depression 3 weeks Favors Comparator Aripiprazole= 10/166 Haloperidol= 3/165 OR = 3.33 (0.98, 15.83) ; P = 0.049 Cases of Manic Reaction or Relapse at Last Measurement 12 weeks Favors Comparator Aripiprazole= 8/166 Haloperidol= 1/165 OR = 7.36 (1.30, 186.76) ; P = 0.037
	Vieta, 2005⁶ 16135860 Moderate	See forest plot above.	YMRS 3 weeks NS Aripiprazole −15.7 Haloperidol =−15.7 No statistical test reported CGI-BP-Sev 3 weeks NS Aripiprazole −2.0 Haloperidol =−1.9 No statistical test reported	NR	See forest plot above.	See forest plot above.

: Abbreviations: AE=Adverse Events; CGI=Clinical Global Impressions Scale; CI=Confidence Interval; NS=not significant; OR=Odds Ratio; YMRS = Young Mania Rating Scale

Appendix Table E6Strength of evidence assessment: aripiprazole versus active comparator for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Aripiprazole vs. haloperidol	Response 3 wk Remission 3 wk YMRS 3 wk Withdrawal	2 RCTs (n=674)	See table above	High	Consistent	Direct	Imprecise	Insufficient

: Abbreviations: CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; NS=not significant; RCT=randomized controlled trial; YMRS = Young Mania Rating Scale
: Notes:
1: Publication bias for antipsychotics, antidepressants, and behavioral interventions for depressive disorders is suspected.
2: Data were generally imprecise due to missing data from high attrition rates, which was commonly dealt with by Last Observation Carried Forward (LOCF). LOCF requires an assumption that the health status of patients who dropped out of the trial would not have changed had future observations been recorded, a strong assumption in the context of bipolar disorder research.

Section 2. Asenapine for Acute Mania

Appendix Table E7Characteristics of eligible studies: asenapine for acute mania

Study, Year Design Location Funder Risk of Bias PMID	# Randomized Age (mean) Sex (% Female) Race (% White) Diagnosis (% BP-I, II, NOS) Setting	Inclusions Key Exclusions	Intervention Dosage	Comparison Dosage	Follow-up Duration	Outcomes Reported Withdrawal (%) at endpoint
Landbloom, 2016⁷ RCT Multisite 3 Continents Industry RoB Moderate 26496015	N = 367 Mean Age 44 Female 55% Race NR BP-I 100% Inpatient (week 1) Outpatient (weeks 2–3	Mania; Structured clinical interview (MINI). Episode began at least 1 month prior to screening. YMRS ≥ 20 First Manic Episode Schizoaffective Substance Abuse Other Mental Health Taking Other Meds Labs/Other Conditions	Asenapine T1: 5 mg BID T2: 10mg BID	Placebo	3 weeks	Response (50% change YMRS scores) Remission (YMRS) YMRS CGI-BP-S PANSS MADRS SAEs EPS Withdrawal 28%
McIntyre, 2010⁸ RCT Multisite 3 Continents Industry RoB High 20096936	N = 488 Mean Age 39 Female 47% White 55% BP-I 100% Inpatient (week 1) Outpatient (weeks 2–3, subject to investigator discretion and successful passing of InterSePT Scale for Suicidal Thinking criteria)	Manic/Mixed; YMRS ≥ 20; Current episode ≤ 3 months First Manic Episode Neurological Disorders Substance Abuse Other Mental Health Taking Other Meds Lab/Other Conditions	Asenapine 10–20 mg/day (18.4 mg/day average) N=185	C1: Placebo n=98 C2: Olanzapine 5–20 mg/day n=205	3 weeks	CGI-BP-S MADRS Remission (YMRS ≤ 12) Remission Rate (YMRS ≤ 12) Response (50% decrease in YMRS) YMRS Withdrawal 34%
McIntyre, 2009⁹ RCT Multisite 3 continents Industry RoB High 19839993	N = 489 Mean Age 39 Female 43% White 61% BP-I 100% Inpatient (week 1) Outpatient (weeks 2–3, subject to investigator discretion and successful passing of InterSePT Scale for Suicidal Thinking criteria)	Manic/Mixed; YMRS ≥ 20; Current episode ≤ 3 months First Manic Episode Neurological Disorders Substance Abuse Taking Other Meds Labs/Other Conditions	Asenapine 10–20 mg/day (18.2 mg/day) N=104	C1: Placebo n=194 C2: Olanzapine 5–20 mg/day n=190	3 weeks	AIMS BARS CGI-BP-S MADRS Remission (YMRS ≤12) Response (50% decrease in YMRS) Simpson-Angus Scale (SAS) YMRS Withdrawal 31%
Calabrese, 2015¹⁰ RCT Multisite 3 Continents Industry RoB Low 25562205	N = 497 Mean Age 42 Female 47% White 69% BP-I 100% Inpatient (weeks 1–2) Outpatient (week 3, subject to inspector discretion)	Manic/Mixed; YMRS ≥20 AND ≥ 4 on two YMRS items; MADRS < 18 First Manic Episode Schizoaffective Substance Abuse Other Mental Health Neurological Disorders Taking Other Meds	Cariprazine I1: 3–6 mg/day I2: 6–12 mg/day	Placebo	3 weeks	CGI-S SAS YMRS Withdrawal 11%
Durgam, 2015¹¹ RCT Multisite 3 Continents Industry RoB Moderate 25056368	N = 238 Mean Age 38 Female 67% White 43% BP-I 100% Inpatient (weeks 1–2) Outpatient (week 3, subject to inspector discretion)	Manic/Mixed; YMRS ≥20 AND ≥4 on two YMRS items First Manic Episode Schizoaffective Substance Abuse Other Mental Health Neurological Disorders Taking Other Meds Pregnant/Nursing Labs/Other Conditions	Cariprazine 3–12 mg/day	Placebo	3 weeks	YMRS MADRS CGI-S CGI-I PANSS AIMS BARS SAS Withdrawal 37%

: Abbreviations: AIMS=Abnormal Involuntary Movement Scale; BARS=Barnes Akathisia Scale; BAS=Behavioral Approach System; BMI=Body Mass Index; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; C=comparison; CGI= Clinical Global Impressions; CGI-I=Clinical Global Impressions-Improvement; CGI-S =CGI-Severity; CGI-BP=Clinical Global Impressions Scale-Bipolar; CGI-BP-C= Clinical Global Impressions, Bipolar, Change Scale; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; C-SSRS=Columbia Suicide Severity Rating Scale; DAI-10=Drug Attitutde Inventory, 10 question version; DIEPSS=Drug-Induced Extra-Pyramidal Symptoms Scale; DSM=Diagnostic and Statistical Manual of Mental Disorders; EPS=extrapyramidal symptoms; ER=Extended Release; ESRS=Extrapyramidal Symptom Rating Scale; GAF=General Assessment of Functioning Scale; GAS=Global Assessment Scale; HAM-A=Hamilton Scale for Anxiety; HAM-D=Hamilton Scale for Depression; HRQL=Health-related quality of life; HRQOL=Health-related quality of life; I=intervention; IDS=Inventory for Depressive Symptoms; LIFE= Longitudinal Interval Follow-up Evaluation; MADRS=Montgomery-Asberg Depression Rating Scale; MAS=Bech-Rafaelsen Mania Rating Scale; MRS=Mania Rating Scale; MSRS=Manic state rating scale; NOS=not otherwise specified; NR=not reported; PANSS=Positive and Negative Syndrome Scale; PRS=Polygenic Risk Scores; PGWB=Psychological General Well-Being Index; PMID=PubMed Identification Number; PRS=Polygenic Risk Scores; Q-LES-Q=Quality of Life Enjoyment and Satisfaction Questionnaire; RCT=randomized controlled trial; ROB=risk of bias; SADS-C= Schedule for Affective Disorders and Schizophrenia-Change version; SAE=Serious Adverse Events; SAS=Simpson Angus Scale; SF-12=12-Item Short Form Health Survey; SF-36=36-Item Short Form Health Survey; SLICE=Streamlined Longitudinal Interview Clinical Evaluation; T=Trial; YMRS = Young Mania Rating Scale

Appendix Table E8Summary risk of bias assessments: asenapine for acute mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Asenapine	McIntyre, 2010¹² Industry 20096936	High	Randomization and blinding procedures not described. Withdrawal 34%.
	McIntyre, 2009⁹ Industry 19839993	High	Randomization and blinding procedures not described. Patients discharged from inpatient care at differing times and study doesn’t include this as a point of analysis as a possible confounder. Withdrawal 31%.
	Landbloom, 2016⁷ Industry 26496015	Low	No sources of bias identified.

: Abbreviations: ITT=Intention to Treat; PMID=PubMed Identification Number; LOCF=last observation carried forward

Asenapine Forest Plots

Appendix Figure E20Asenapine vs. placebo – response

Appendix Figure E21Asenapine vs. placebo - remission

Appendix Figure E22Asenapine vs. placebo – YMRS

Appendix Figure E23Asenapine vs. placebo – CGI-BP-S

Appendix Figure E24Asenapine vs. placebo – withdrawal lack of efficacy

Appendix Figure E25Asenapine vs. placebo – withdrawal adverse events

Appendix Figure E26Asenapine vs. placebo – overall withdrawal

Appendix Table E9Outcomes summary: asenapine versus placebo for acute mania

Drug	Study PMID RoB	Responder/Remitter	Symptom	Function	Other	AE
Asenapine	McIntyre, 2010¹² Industry 20096936	See forest plot E20 above for response.	See forest plot E22 above for YMRS.	See forest plot E23 above for CGI.	See forest plots E24, E25, E26 above for Withdrawals. 1 suicide in asenapine	SAE Placebo: 3.8% Asenapine: 1.5% NS EPS (<1) Placebo: 3.1% Asenapine: 10.3% p=0.03 Weight gain ≥7% Placebo: 1.2% Asenapine: 7.2% p=0.03
	McIntyre, 2009⁹ Industry 19839993	See forest plot E20 above for response.	See forest plot E22 above for YMRS.	See forest plot E32 above for CGI.	See forest plots E24, E25, E26 above for Withdrawals.	SAE Placebo: 3.8% Asenapine: 1.5% NS EPS (<1) Placebo: 3.1% Asenapine: 10.3% p=0.03 Weight gain ≥7% Placebo: 1.2% Asenapine: 7.2% p=0.03
	Landbloom, 2016⁷ Industry 26496015	See forest plot E20 above for response.	See forest plot E22 above for YMRS.	See forest plot E32 above for CGI.	See forest plots E24, E25, E26 above for Withdrawals. Suicide Ideation Placebo: 5/126 5 mg Asenapine: 4/122 10 mg Asenapine: 1/129 NS	SAE “Most…were psychiatric disorders class” Placebo: 2/126 5 mg Asenapine: 3/122 10 mg Asenapine: 1/119 NS EPS Placebo: 6/126 5 mg Asenapine: 8/122 10 mg Asenapine: 25/129 p<0.0001 10 mg

: Abbreviations: AE=Adverse Events; ANCOVA=Analysis of Covariance; CGI=Clinical Global Impressions Scale; CI=Confidence Interval; EPS=extrapyramidal symptoms; ESRS=Extrapyrimidal Symptom Rating Scale; GAS=Global Assessment Scale; MADRS=Montgomery-Asberg Depression Rating Scale; NR=c; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; ROB=Risk of Bias; SAE=Serious Adverse Events; YMRS = Young Mania Rating Scale

Appendix Table E10Strength of evidence assessment: asenapine versus placebo for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Asenapine vs. placebo	Response Remission 3 wks	3 RCT (n=936)	NS	Moderate	Consistent	Direct	Imprecise	Low
	YMRS 3 wks	3 RCT (n=936)	Favors Asenapine. MD 4.37 (1.27, 7.47)	Moderate	Consistent	Direct	Imprecise	Low
	CGI-BP-S 3 wk	3 RCT (n=936)	Favors Asenapine MD 0.5 (0.29, 0.71)	Moderate	Consistent	Direct	Imprecise	Low
	Withdrawal – AE, Lack of Efficacy, Overall	3 RCT (n=936)	NS	Moderate	Consistent	Direct	Imprecise	Low

: Abbreviations: CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; NS=not significant; RCT=randomized controlled trial; YMRS = Young Mania Rating Scale
: Notes:
1: Publication bias for antipsychotics, antidepressants, and behavioral interventions for depressive disorders is suspected.
2: Data were generally imprecise due to missing data from high attrition rates, which was commonly dealt with by Last Observation Carried Forward (LOCF). LOCF requires an assumption that the health status of patients who dropped out of the trial would not have changed had future observations been recorded, a strong assumption in the context of bipolar disorder research.

Appendix Table E11Outcomes summary: asenapine versus active comparator for acute mania

Comparison	Study PMID RoB	Responder/Remitter	Symptom	Function	Other	AE
Asenapine vs. olanzapine	McIntyre, 2009⁹ 19839993	Response 3 weeks Asenapine 42.3% Olanzapine 50% Remission 3 weeks Asenapine 40.2% Olanzapine 39.4% NS	YMRS 3 weeks Least square mean Asenapine −10.8 SD 0.8 (effect size 0.45) Olanzapine −12.6 SD 0.8 (effect size 0.70)	CGI 3 weeks Least square mean Asenapine −1.2 SD 0.01 Olanzapine −1.4 SD 0.01	NR Overall Withdrawal Asenapine 37.1% Olanzapine 30.9% Withdrawal Lack of Efficacy: Asenapine 8.2% Olanzapine 5.8% Withdrawal AE Asenapine 10.3% Olanzapine 4.2%	Serious Adverse Events 3 weeks 0 in all arms Deaths 3 weeks 0 in all arms EPS 3 weeks 2.9% placebo 7.2% Asenapine 7.9% Olanzapine
Asenapine vs. olanzapine	McIntyre, 2010¹² 20096936	Response 3 weeks Asenapine 42.6% Olanzapine 54.7% Remission 3 weeks Asenapine 35.5% Olanzapine 46.3% NS	YMRS 3 weeks Least square mean Asenapine −11.5 SD 0.8 (effect size 0.32) Olanzapine −14.6 SD 0.8 (effect size 0.63)	CGI 3 weeks Least square mean Asenapine −1.2 SD 0.10 Olanzapine −1.5 SD 0.09	NR Overall Withdrawal Asenapine 33.0% Olanzapine 21.5% Withdrawal Lack of Efficacy: Asenapine 7.6% Olanzapine 6.3% Withdrawal AE Asenapine 9.2% Olanzapine 3.4%	Serious Adverse Events 3 weeks 1 Asenapine Deaths 3 weeks 1 Asenapine – suicide EPS 3 weeks 3.1% placebo 10.3% Asenapine 6.8% Olanzapine

: Abbreviations: CGI=Clinical Global Impressions; EPS=extrapyramidal symptoms; NR=not reported; NS=not significant; RCT=randomized controlled trial; YMRS = Young Mania Rating Scale

Appendix Table E12Strength of evidence assessment: asenapine versus active comparator for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Asenapine vs. olanzapine	Response 3 wk Remission 3 wk YMRS 3 wk CGI Withdrawal	2 RCTs (n=763)	See table above	High	Consistent	Direct	Imprecise	Insufficient

: Abbreviations: CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; NS=not significant; RCT=randomized controlled trial; YMRS = Young Mania Rating Scale
: Notes:
1: Publication bias for antipsychotics, antidepressants, and behavioral interventions for depressive disorders is suspected.
2: Data were generally imprecise due to missing data from high attrition rates, which was commonly dealt with by Last Observation Carried Forward (LOCF). LOCF requires an assumption that the health status of patients who dropped out of the trial would not have changed had future observations been recorded, a strong assumption in the context of bipolar disorder research.

Section 3. Cariprazine for Acute Mania

Appendix Table E13Characteristics of eligible studies: cariparazine for acute mania

Study, Year Design Location Funder Risk of Bias PMID	# Randomized Age (mean) Sex (% Female) Race (% White) Diagnosis (% BP-I, II, NOS) Setting	Inclusions Key Exclusions	Intervention Dosage	Comparison Dosage	Follow-up Duration	Outcomes Reported Withdrawal (%) at endpoint
Calabrese, 201510 RCT Multisite 3 Continents Industry RoB Low 25562205	N = 497 Mean Age 42 Female 47% White 69% BP-I 100% Inpatient (weeks 1–2) Outpatient (week 3, subject to inspector discretion)	Manic/Mixed; YMRS ≥20 AND ≥ 4 on two YMRS items; MADRS < 18 First Manic Episode Schizoaffective Substance Abuse Other Mental Health Neurological Disorders Taking Other Meds	Cariprazine I1: 3–6 mg/day I2: 6–12 mg/day	Placebo	3 weeks	CGI-S SAS YMRS Withdrawal 11%
Durgam, 201511 RCT Multisite 3 Continents Industry RoB Moderate 25056368	N = 238 Mean Age 38 Female 67% White 43% BP-I 100% Inpatient (weeks 1–2) Outpatient (week 3, subject to inspector discretion)	Manic/Mixed; YMRS ≥20 AND ≥4 on two YMRS items First Manic Episode Schizoaffective Substance Abuse Other Mental Health Neurological Disorders Taking Other Meds Pregnant/Nursing Labs/Other Conditions	Cariprazine 3–12 mg/day	Placebo	3 weeks	YMRS MADRS CGI-S CGI-I PANSS AIMS BARS SAS Withdrawal 37%
Sachs, 201513 RCT Multisite 2 Continents Industry RoB Moderate 25532076	N = 312 Mean Age 36 Female 36% White 21% BP-I 100% Inpatient (weeks 1–2) Outpatient (week 3, subject to inspector discretion)	Manic/Mixed; YMRS ≥20 AND ≥4 on two YMRS items; MADRS <18 Schizoaffective Substance Abuse Other Mental Health Neurological Disorders Taking Other Meds Pregnant/Nursing	Cariprazine 3–12 mg/day	Placebo	3 weeks	YMRS CGI-S CGI-I MADRS PANSS C-SSRS AIMS BARS SAS Withdrawal 31%

: Abbreviations: AIMS=Abnormal Involuntary Movement Scale; BARS=Barnes Akathisia Scale; BAS=Behavioral Approach System; BMI=Body Mass Index; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; C=comparison; CGI= Clinical Global Impressions; CGI-I=Clinical Global Impressions-Improvement; CGI-S =CGI-Severity; CGI-BP=Clinical Global Impressions Scale-Bipolar; CGI-BP-C= Clinical Global Impressions, Bipolar, Change Scale; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; C-SSRS=Columbia Suicide Severity Rating Scale; DAI-10=Drug Attitutde Inventory, 10 question version; DIEPSS=Drug-Induced Extra-Pyramidal Symptoms Scale; DSM=Diagnostic and Statistical Manual of Mental Disorders; EPS=extrapyramidal symptoms; ER=Extended Release; ESRS=Extrapyramidal Symptom Rating Scale; GAF=General Assessment of Functioning Scale; GAS=Global Assessment Scale; HAM-A=Hamilton Scale for Anxiety; HAM-D=Hamilton Scale for Depression; HRQL=Health-related quality of life; HRQOL=Health-related quality of life; I=intervention; IDS=Inventory for Depressive Symptoms; LIFE= Longitudinal Interval Follow-up Evaluation; MADRS=Montgomery-Asberg Depression Rating Scale; MAS=Bech-Rafaelsen Mania Rating Scale; MRS=Mania Rating Scale; MSRS=Manic state rating scale; NOS=not otherwise specified; NR=not reported; PANSS=Positive and Negative Syndrome Scale; PRS=Polygenic Risk Scores; PGWB=Psychological General Well-Being Index; PMID=PubMed Identification Number; PRS=Polygenic Risk Scores; Q-LES-Q=Quality of Life Enjoyment and Satisfaction Questionnaire; RCT=randomized controlled trial; ROB=risk of bias; SADS-C= Schedule for Affective Disorders and Schizophrenia-Change version; SAE=Serious Adverse Events; SAS=Simpson Angus Scale; SF-12=12-Item Short Form Health Survey; SF-36=36-Item Short Form Health Survey; SLICE=Streamlined Longitudinal Interview Clinical Evaluation; T=Trial; YMRS = Young Mania Rating Scale

Appendix Table E14Summary risk of bias assessments: cariprazine for acute mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Cariprazine	Durgam, 2015¹¹ Industry 25056368	Moderate	The large dropout rate is likely to create some bias. Lack of disclosure of methods to allocate and protect the blind also increases the risk.
	Calabrese, 2015¹⁰ Industry 25562205	Low	Procedures for concealing allocation and blinding participants and providers are not described, but, the study appears to have been well executed, fully reported, and investigators have taken steps to ensure bias was minimized, like pattern mixture modeling.
	Sachs, 2015¹³ Industry 25532076	Moderate	A moderately high dropout rate combined with a lack of disclosure for the methods of allocation and concealment create strong conditions where bias may be present.

: Abbreviations: ITT=Intention to Treat; PMID=PubMed Identification Number; LOCF=last observation carried forward

Cariprazine Forest Plots

Appendix Figure E27Cariprazine vs. placebo – response

Appendix Figure E28Cariprazine vs. placebo - remission

Appendix Figure E29Cariprazine vs. placebo – YMRS

Appendix Figure E30Cariprazine vs. placebo – CGI-BP-S

Appendix Figure E31Cariprazine vs. placebo – withdrawal lack of efficacy

Appendix Figure E32Cariprazine vs. placebo – withdrawal adverse events

Appendix Figure E33Cariprazine vs. placebo – overall withdrawal

Appendix Table E15Outcomes summary: cariprazine versus placebo for acute mania

Drug	Study PMID RoB	Responder/Remitter	Symptom	Function	Other	AE
Cariprazine	Durgam, 2015¹¹ Industry 25056368	See forest plot E27 above for response.	See forest plot E29 above for YMRS.	See forest plot E30 above for CGI.	See forest plots E31, E32, E33 above for Withdrawals.	SAE Placebo: 5 patients Cariprazine: 4 patients No suicide attempts No difference between groups in suicide ideation EPS Placebo: 1% Cariprazine groups: 11% or 14% Akasthesia Placebo: 4% Cariprazine groups:20% or 23%
	Calabrese, 2015¹⁰ Industry 25562205	See forest plot E27 above for response.	See forest plot E29 above for YMRS.	See forest plot E30 above for CGI.	See forest plots E31, E32, E33 above for Withdrawals.	SAE Placebo: 0 patients Cariprazine: 4 patients No suicide attempts I placebo patients reported suicide ideation EPS Placebo: 1 patient Cariprazine: 19 patients Akasthesia Placebo: 7 patient Cariprazine: 26 patients
	Sachs, 2015¹³ Industry 25532076	See forest plot E27 above for response.	See forest plot E29 above for YMRS.	See forest plot E30 above for CGI.	See forest plots E31, E32, E33 above for Withdrawals.	SAE Placebo: 3 patients Cariprazine: 5 patients No suicide attempts No difference between groups in suicide ideation EPS Placebo: 6 patients Cariprazine: 30 patients Akasthesia Placebo: 8 patient Cariprazine: 36 patients

: Abbreviations: AE=Adverse Events; ANCOVA=Analysis of Covariance; CGI=Clinical Global Impressions Scale; CI=Confidence Interval; EPS=extrapyramidal symptoms; ESRS=Extrapyrimidal Symptom Rating Scale; GAS=Global Assessment Scale; MADRS=Montgomery-Asberg Depression Rating Scale; NR=Not reported; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; ROB=Risk of Bias; SAE=Serious Adverse Events; YMRS = Young Mania Rating Scale

Appendix Table E16Strength of evidence assessment: cariprazine versus placebo for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Cariprazine vs. placebo	Response 3 wks	3 RCT (n=1,047)	Favors Cariprazine OR 2.14 (95% CI 1.08, 4.23)	Moderate	Consistent	Direct	Imprecise	Low
	Remission 3 wks	3 RCT (n=1,047)	Favors Cariprazine OR 1.95 (95% CI 1.45, 2.63)	Moderate	Consistent	Direct	Imprecise	Low
	YMRS 3 wks	3 RCT (n=1,047)	Favors Cariprazine MD 5.38 (95% CI 1.84, 8.92)	Moderate	Consistent	Direct	Imprecise	Low
	CGI-BP-S 3 wk	3 RCT (n=1,047)	Favors Cariprazine MD 0.54 (95% CI 0.35, 0.73)	Moderate	Consistent	Direct	Imprecise	Low
	Withdrawal – AE, Lack of Efficacy, Overall	3 RCT (n=1,047)	NS	Moderate	Consistent	Direct	Imprecise	Low

: Abbreviations: CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; NS=not significant; RCT=randomized controlled trial; YMRS = Young Mania Rating Scale
: Notes:
1: Publication bias for antipsychotics, antidepressants, and behavioral interventions for depressive disorders is suspected.
2: Data were generally imprecise due to missing data from high attrition rates, which was commonly dealt with by Last Observation Carried Forward (LOCF). LOCF requires an assumption that the health status of patients who dropped out of the trial would not have changed had future observations been recorded, a strong assumption in the context of bipolar disorder research.

Section 4. Haloperidol for Acute Mania

Appendix Table E17Characteristics of eligible studies: haloperidol for acute mania

Study, Year Design Location Funder Risk of Bias PMID	# Randomized Age (mean) Sex (% Female) Race (% White) Diagnosis (% BP-I, II, NOS) Setting	Inclusions Key Exclusions	Intervention Dosage	Comparison Dosage	Follow-up Duration	Outcomes Reported Withdrawal (%) at endpoint
McIntyre, 2005¹⁴ RCT Multisite 3 Continents Industry Moderate 16139175	N = 299 Mean Age 42 Female 63% Race NR BP-I 100% Inpatient	Manic YMRS ≥ 20 CGI–BP ≥4 First Manic Episode Substance Abuse Neurological Disorders Taking Other Meds Pregnant/Nursing Labs/Other Conditions	Haloperidol Starting 2mg/day up to 8mg/day	C1: Placebo C2: Quetiapine 100mg/day increasing by 100mg up to 800 mg/day	12 weeks	Remission Rates Adverse Events Efficacy YMRS CGI PANSS MADRS GAS Withdrawal 50%
Smulevich, 2005¹⁵ RCT Multisite Location NR Industry Moderate 15572276	N = 438 Mean Age 40 Female 47% White 65% BP-I 100% Outpatient	Manic YMRS ≥ 20 MADRS ≤ 20 First Manic Episode Schizoaffective Substance Abuse Other Mental Health Taking Other Meds	Haloperidol Initiated at 4mg/day increased by 2mg/day up to 12 mg/day	C1: Placebo C2: Risperidone Initiated at 2mg/day increased by 1mg/day up to 6mg/day	12 weeks (12 week outcomes excluded due to attrition of Haloperidol arm)	Efficacy YMRS CGI GAS MADRS BPRS Extrapyramidal symptoms ESRS Withdrawal 48% at 12 weeks 12% at 3 weeks

: Abbreviations: AIMS=Abnormal Involuntary Movement Scale; BARS=Barnes Akathisia Scale; BAS=Behavioral Approach System; BMI=Body Mass Index; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; C=comparison; CGI= Clinical Global Impressions; CGI-I=Clinical Global Impressions-Improvement; CGI-S =CGI-Severity; CGI-BP=Clinical Global Impressions Scale-Bipolar; CGI-BP-C= Clinical Global Impressions, Bipolar, Change Scale; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; C-SSRS=Columbia Suicide Severity Rating Scale; DAI-10=Drug Attitutde Inventory, 10 question version; DIEPSS=Drug-Induced Extra-Pyramidal Symptoms Scale; DSM=Diagnostic and Statistical Manual of Mental Disorders; EPS=extrapyramidal symptoms; ER=Extended Release; ESRS=Extrapyramidal Symptom Rating Scale; GAF=General Assessment of Functioning Scale; GAS=Global Assessment Scale; HAM-A=Hamilton Scale for Anxiety; HAM-D=Hamilton Scale for Depression; HRQL=Health-related quality of life; HRQOL=Health-related quality of life; I=intervention; IDS=Inventory for Depressive Symptoms; LIFE= Longitudinal Interval Follow-up Evaluation; MADRS=Montgomery-Asberg Depression Rating Scale; MAS=Bech-Rafaelsen Mania Rating Scale; MRS=Mania Rating Scale; MSRS=Manic state rating scale; NOS=not otherwise specified; NR=not reported; PANSS=Positive and Negative Syndrome Scale; PRS=Polygenic Risk Scores; PGWB=Psychological General Well-Being Index; PMID=PubMed Identification Number; PRS=Polygenic Risk Scores; Q-LES-Q=Quality of Life Enjoyment and Satisfaction Questionnaire; RCT=randomized controlled trial; ROB=risk of bias; SADS-C= Schedule for Affective Disorders and Schizophrenia-Change version; SAE=Serious Adverse Events; SAS=Simpson Angus Scale; SF-12=12-Item Short Form Health Survey; SF-36=36-Item Short Form Health Survey; SLICE=Streamlined Longitudinal Interview Clinical Evaluation; T=Trial; YMRS = Young Mania Rating Scale

Appendix Table E18Summary risk of bias assessments: haloperidol for acute mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Haloperidol	McIntyre, 2005¹⁶ Industry 16139175	High	High dropout rates (46% overall) create a likelihood of bias, lacks some core information on how allocation was concealed and blinding of treatment staff and raters was maintained.
	Smulevich, 2005¹⁵ Industry 15572276	Moderate	Open drugs given to some participants. Pools results for blinded and unblinded without establishing similarity of groups
	Sachs, 2002¹⁷ Industry 12091192	High	Lacks randomization and blinding procedures. High dropout rates across all arms (46% overall)
	Vieta, 2010¹⁸ Industry 20565430	High	Large dropout rate among all study arms, across all time periods; raters may not be blinded

: Abbreviations: ITT=Intention to Treat; PMID=PubMed Identification Number; LOCF=last observation carried forward

Haloperidol Forest Plots

Appendix Figure E34Haloperidol vs. placebo – response

Appendix Figure E35Haloperidol vs. placebo – YMRS

Appendix Figure E36Haloperidol vs. placebo – CGI-BP-S

Appendix Figure E37Haloperidol vs. placebo – withdrawal lack of efficacy

Appendix Figure E38Haloperidol vs. placebo – withdrawal adverse events

Appendix Figure E39Haloperidol vs. placebo – overall withdrawal

Appendix Table E19Outcomes summary table: haloperidol versus placebo for acute mania

Drug	Study PMID RoB	Responder/Remitter	Symptom	Function	Other	AE
Haloperidol	McIntyre, 2005¹⁴ 16139175 High	Response See forest plot E34 above for response Remission NS	See forest plot E35 above for YMRS	See forest plot E36 for CGI	See forest plot E37, E38, E39 above for Withdrawals	SAE No reported serious events EPS Haloperidol 35.4% Placebo 5.9% P<0.001 Weight gain 7% NS
Haloperidol	Smulevich, 2005¹⁵ 15572276 Moderate	Response See forest plot E34 above for response Remission	See forest plot E35 above for YMRS	See forest plot E36 for CGI GAS 3 week Placebo −10.3(1.7) Haloperidol −13.9(10.3) No Statistical Tests reported GAS 12 week Placebo Haloperidol No Statistical Tests reported	See forest plot E37, E38, E39 above for Withdrawals	No reported SAE

: Abbreviations: AE=Adverse Events; ANCOVA=Analysis of Covariance; CGI=Clinical Global Impressions Scale; CI=Confidence Interval; EPS=extrapyramidal symptoms; ESRS=Extrapyrimidal Symptom Rating Scale; GAS=Global Assessment Scale; MADRS=Montgomery-Asberg Depression Rating Scale; NR=Not reported; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; ROB=Risk of Bias; SAE=Serious Adverse Events; YMRS = Young Mania Rating Scale

Appendix Table E20Strength of evidence assessment: Haloperidol versus placebo for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Haloperidol vs. placebo	Relapse 3 wks YMRS CGI-BP-S Withdrawals	2 RCTs (n=483)	See forest plots	High	Consistent	Direct	Imprecise	Insufficient

: Abbreviations: CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; NS=not significant; RCT=randomized controlled trial; YMRS = Young Mania Rating Scale
: Notes:
1: Publication bias for antipsychotics, antidepressants, and behavioral interventions for depressive disorders is suspected.
2: Data were generally imprecise due to missing data from high attrition rates, which was commonly dealt with by Last Observation Carried Forward (LOCF). LOCF requires an assumption that the health status of patients who dropped out of the trial would not have changed had future observations been recorded, a strong assumption in the context of bipolar disorder research.

Section 5. Olanzapine for Acute Mania

Appendix Table E21Characteristics of eligible studies: olanzapine for acute mania

Study, Year Design Location Funder Risk of Bias PMID	# Randomized Age (mean) Sex (% Female) Race (% White) Diagnosis (% BP-I, II, NOS) Setting	Inclusions Key Exclusions	Intervention Dosage	Comparison Dosage	Follow-up Duration	Outcomes Reported Withdrawal (%) at endpoint
Xu, 2015¹⁹ RCT Single-site Government RoB Low 26060401	N = 120 Mean Age 31 Female 52% Race NR BP-I 100% Setting NR	First manic; YMRS ≥ 17 Substance Abuse Neurological Disorders Taking Other Meds Pregnant/Nursing	Olanzapine 10 mg/day Flexible dosing 5–20 mg/day	C1: Olanzapine 10 mg/day + Valproate 600 mg/day C2: Valproate 600 mg/day alone	4 weeks	Efficacy YMRS CGI-BP Adverse events Extrapyramidal symptoms SAS Withdrawal 5%
Katagiri, 2012²⁰ RCT Single Site Japan Industry RoB Moderate 22134043	N = 221 Mean Age 45 Female 55% Race NR BP-I 100% Outpatient	Manic or Mixed Episode YMRS ≥ 20 Other Mental Health Taking Other Meds Labs/Other Conditions	Olanzapine Initiated at 10mg/day (5–20mg/day)	Placebo (Haloperidol arm not used <10 per arm completed)	3 weeks (6 week not abstracted due to attrition)	Adverse Events Extrapyramidal symptoms DIEPSS Efficacy YMRS HAM-D CGI Withdrawal 41% at 3 weeks 52% at 6 weeks
Vieta, 2012²¹ RCT Multisite 4 Continents Industry RoB High 22503488	N = 560 Mean Age 37 Female 52% White 41% BP-I 100% Outpatient	Manic or Mixed Episode; Acute (YMRS ≥ 20 and CGI-S ≥ 4) or non-acute (mood episodes with YMRS <12 and CGI-S ≤3)	Olanzapine 10 mg/day	C1: Placebo C2: Risperidone long-acting injectable (25–50 mg)	12 weeks (18 month extension for participants without mood recurrence)	Response (YMRS ≤ 19) Time to first recurrence of mood symptoms Efficacy YMRS CGI-S MADRS Adverse events Extrapyramidal symptoms ESRS Withdrawal 29%
McIntyre, 2010⁸ RCT Multisite 3 Continents Industry RoB High 20096936	N = 488 Mean Age 39 Female 47% White 55% BP-I 100% Inpatient and Outpatient	Manic or Mixed Episode; YMRS ≥ 20 First Manic Episode Schizoaffective Substance Abuse Other Mental Health Neurological Disorders Taking Other Meds Pregnant/Nursing Labs/Other Conditions	Olanzapine 5–20 mg/day	C1: Placebo C2: Asenapine 5–10 mg/2 times daily	3 weeks	Response (≥ 50% YMRS reduction) Time to response (days from baseline to ≥50% YMRS reduction) Remission (≤ 12 YMRS) Efficacy YMRS CGI (BP and mania subscales) MADRS Adverse events Extrapyramidal symptoms SAS BAS AIMS Withdrawal 34%
Shafti, 2010 RCT Iran Funding NR RoB Moderate 19740546	N = 40 Age NR Female 100%; Race NR BP-I 100% Inpatient	Manic (not described) Schizoaffective Substance Abuse Other Mental Health Neurological Disorders Taking Other Meds Labs/Other Conditions	Olanzapine 5 mg/day	Lithium 300 mg/day	12 weeks	MSRS CGI-S Adverse events Extrapyramidal symptoms Withdrawal 13%
McIntyre, 2009 RCT Multisite 3 Continents Industry RoB High 19839993	N = 489 Mean Age 40 Female 43% White 61% BP-I 100% Inpatient and Outpatient	Manic or Mixed Episode; YMRS ≥ 20 Schizoaffective Substance Abuse Other Mental Health Neurological Disorders Taking Other Meds Pregnant/Nursing Labs/Other Conditions	Olanzapine 5–20 mg/day	C1: Placebo C2: Asenapine 5–10 mg/2 times daily	3 weeks	Response (YMRS, cutoff NR) Remission (YMRS, cutoff NR) Efficacy YMRS CGI (multiple subscales) MADRS Adverse events Extrapyramidal symptoms SAS BAS AIMS Withdrawal 31%
Niufan, 2008²² RCT Multisite China Industry RoB Low 17531327	N = 140 Mean Age 33 Female 74% Race NR Diagnosis NR Outpatient	Manic or Mixed Episode; YMRS ≥ 20 NR	Olanzapine 15 mg/day Flexible dosing 5–20 mg/day	Lithium Carbonate 300–600 mg/day Flexible dosing 600–1800 mg/day divided dose	4 weeks	Efficacy YMRS CGI BPRS MADRS Extrapyramidal symptoms SAS Withdrawal 15%
Tohen, 2008b²³ RCT 3 Continents Industry RoB Low 19014751	N = 521 Mean Age 40 Female 49% Race NR Diagnosis NR Inpatient and Outpatient	Manic or Mixed Episode; YMRS 20–30 CGI-BP mania 3–4 Schizoaffective Other Mental Health Pregnant/Nursing	Olanzapine 5–20 mg/day	C1: Placebo C2: Divalproex 500–2500 mg/2–3 times daily	12 weeks	Response (≥ 50% YMRS reduction) Time to response (days from baseline to ≥ 50% YMRS reduction) Remission (≤ 12 YMRS) Efficacy YMRS CGI (multiple subscales) MADRS Adverse events Extrapyramidal symptoms SAS BAS AIMS Withdrawal 26%
Perlis, 2006²⁴ RCT Multisite US Industry RoB High 17196055	N = 329 Mean Age 38 Female 55% White 74% BP-I 100% Outpatient	Manic; YMRS ≥ 20 Substance Abuse Labs/Other Conditions	Olanzapine 5–20 mg/day	Risperidone 1–6 mg/day	3 weeks	Efficacy YMRS MADRS CGI HAM-D DAI-10 PGWB SF-12 Extrapyramidal symptoms BAS Simpson-Angus Withdrawal 27%
Revicki, 2003²⁵ RCT Multisite US Industry RoB Moderate 12716270 Secondary analysis of Zajecka 2002 [PMID 12523875]	N = 52 Mean Age 38 Female 56% White 81% BP-I 100% Inpatient and outpatient	Manic; YMRS ≥ 25	Olanzapine 20 mg/day	Divalproex 20 mg/kg/day up to an additional 1000 mg/day	12 weeks (6 and 12 week outcomes excluded due to attrition)	Efficacy YMRS Quality of Life HRQL Q-LES-Q Medical Resource Use Cost Withdrawal (base study Zajecka, 2002 reports withdrawal of 69% at 12 weeks, Revicki reports 35% withdrawal at 3 weeks)
Tohen, 2003²⁶ RCT Multisite 4 Continents Industry RoB Moderate 14662554 12177585²⁷	N = 453 Mean Age 40 Female 60% Race NR BP-I 100% Inpatient or outpatient	Manic; YMRS ≥ 20 Substance Abuse Labs/Other Conditions	Olanzapine 15 mg/day flex dosing 5, 10,15, or 20 mg/day	Haloperidol 10 mg/day flex dosing 3, 5, 10, or 15 mg/day	12 weeks	Illness Severity YMRS HAM-D Quality of Life SF-36 Extrapyramidal Symptoms AIMS BAS Remission Adverse Events Withdrawal 43%
Tohen, 2002b²⁸ RCT Multisite US Industry RoB High 12042191	N = 251 Mean Age 41 Female 57% White 81% BP-I 100% Outpatient	Mania; YMRS ≥ 20 Substance Abuse Other Mental Health Neurological Disorders Taking Other Meds Pregnant/Nursing Labs/Other Conditions	Olanzapine 15 mg/day with flexible dosing from 5–20 mg/day	Divalproex 750mg/day with flexible dosing from 500–2500 mg/day	3 weeks	Efficacy YMRS HAM-D Remission Adverse Events Extrapyramidal symptom Withdrawal 34%
Tohen, 2000²⁹ RTC Multisite US Industry RoB High 10986547	N = 115 Mean Age 39 Female 50% White 80% Diagnosis NR Inpatient (week 1) Outpatient (after week 1 if CGI-BP ≤3)	Mixed Episode; YMRS score ≥ 20 Substance Abuse; Other Mental Health; Neurological Disorders; Taking Other Meds; Labs/Other Conditions	Olanzapine 15 mg/day (adjusted between 5–20 mg/day)	Placebo	4 weeks	Symptom Severity YMRS HAM-D CGI PANSS Safety EPS Adverse Events Withdrawal 49%
Berk, 1999³⁰ RCT Single-Site South Africa University RoB High 10565800	N = 30 Mean Age 31 Sex NR Race NR Diagnosis NR Inpatient	Mania (no other inclusion criteria provided) Other Mental Health; Pregnant/Nursing; Labs/Other Conditions	Olanzapine 10 mg/day	Lithium 400mg twice /day	4 weeks	Psychiatric Condition PRS CGI MAS Functioning GAF Side Effects SAS Withdrawal NR

: Abbreviations: AIMS=Abnormal Involuntary Movement Scale; BARS=Barnes Akathisia Scale; BAS=Behavioral Approach System; BMI=Body Mass Index; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; C=comparison; CGI= Clinical Global Impressions; CGI-I=Clinical Global Impressions-Improvement; CGI-S =CGI-Severity; CGI-BP=Clinical Global Impressions Scale-Bipolar; CGI-BP-C= Clinical Global Impressions, Bipolar, Change Scale; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; C-SSRS=Columbia Suicide Severity Rating Scale; DAI-10=Drug Attitutde Inventory, 10 question version; DIEPSS=Drug-Induced Extra-Pyramidal Symptoms Scale; DSM=Diagnostic and Statistical Manual of Mental Disorders; EPS=extrapyramidal symptoms; ER=Extended Release; ESRS=Extrapyramidal Symptom Rating Scale; GAF=General Assessment of Functioning Scale; GAS=Global Assessment Scale; HAM-A=Hamilton Scale for Anxiety; HAM-D=Hamilton Scale for Depression; HRQL=Health-related quality of life; HRQOL=Health-related quality of life; I=intervention; IDS=Inventory for Depressive Symptoms; LIFE= Longitudinal Interval Follow-up Evaluation; MADRS=Montgomery-Asberg Depression Rating Scale; MAS=Bech-Rafaelsen Mania Rating Scale; MRS=Mania Rating Scale; MSRS=Manic state rating scale; NOS=not otherwise specified; NR=not reported; PANSS=Positive and Negative Syndrome Scale; PRS=Polygenic Risk Scores; PGWB=Psychological General Well-Being Index; PMID=PubMed Identification Number; PRS=Polygenic Risk Scores; Q-LES-Q=Quality of Life Enjoyment and Satisfaction Questionnaire; RCT=randomized controlled trial; ROB=risk of bias; SADS-C= Schedule for Affective Disorders and Schizophrenia-Change version; SAE=Serious Adverse Events; SAS=Simpson Angus Scale; SF-12=12-Item Short Form Health Survey; SF-36=36-Item Short Form Health Survey; SLICE=Streamlined Longitudinal Interview Clinical Evaluation; T=Trial; YMRS = Young Mania Rating Scale

Appendix Table E22Summary risk of bias assessments: olanzapine for acute mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Olanzapine	Xu, 2015¹⁹ Government 26060401	Low	Well-constructed, described, and reported study. 5% dropout.
	Katagiri, 2012³¹ Industry 22134043	Moderate	Appears to be completely reported and generally well executed, however, dropout rates and LOCF create substantial possibility for bias.
	Vieta, 2012³² Industry 22503488	High	High - blinding and randomization procedures not well described. Period II results are biased by the drug assignment being open label. Period three efficacy scores are likely to be biased by the large non-completer rate.
	McIntyre, 2010¹² Industry 20096936	High	Randomization and blinding procedures not described. 34% dropout.
	Shafti, 2010³³ Funding NR 19740546	Moderate	Randomization and blinding procedures not described. 13% dropout
	McIntyre, 2009⁹ Industry 19839993	High	Randomization and blinding procedures not described. Patients discharged from hospital at differing times and doesn’t account for this as a possible confounder. 31% overall dropout with high differential dropout between olanzapine and other groups.
	Niufan, 2008²² Industry 17531327	Low	Randomization procedure not described. Medication and rater blinded. 16% dropout.
	Tohen, 2008b²³ Industry 19014751	Low	Well-constructed and described study. No obvious sources of bias present. 26% dropout.
	Perlis, 2006³⁴ Industry 17196055	High	Randomization and blinding procedure not described. 27% dropout.
	Revicki, 2003²⁵ Industry 12716270	Moderate	Randomization and blinding procedures not described. 35% before 3 weeks, 52/120 complete 12 week study. Study notes consistency in traits between dropouts and those who complete, which may be an indication that outcomes may be less biased.
	Tohen, 2003²⁶ Industry 14662554	Moderate	Randomization procedure not described. 43% dropout.
	Shi, 2002²⁷ Industry 12177585	High	Randomization procedure not described, although does note “randomization codes”. States that 166 olanz and 141 halo complete 6 weeks and 140 olanz and 116 halo complete 12 weeks. The counts of patients who complete the follow-up assessments do not match these numbers, in some cases quite substantially. Missing patients not accounted for. Described in the methods that only patients who completed the questionnaire and provided data about the change from baseline to endpoint were included - not ITT.
	Tohen, 2002b²⁸ Industry 12042191	High	Randomization and blinding procedures not described. 33% dropout.
	Tohen, 2000²⁹ Industry 10986547	High	Blinding procedures not described. Responders allowed to leave hospital, non-responders were not. 49% Dropout.
	Berk, 1999³⁰ University 10565800	High	Randomization and blinding procedures not described. Does not describe handling of participants who drop out. Notes that the groups were matched at baseline by education, marital status, ethnicity, employment status but offers no details on these demographic rates.

: Abbreviations: ITT=Intention to Treat; PMID=PubMed Identification Number; LOCF=last observation carried forward

Olanzapine Forest Plots

Appendix Figure E40Olanzapine vs. placebo – response

Appendix Figure E41Olanzapine vs. placebo – remission

Appendix Figure E42Olanzapine vs. placebo – YMRS

Appendix Figure E43Olanzapine vs. placebo – CGI

Appendix Figure E44Olanzapine vs. placebo – overall withdrawal

Appendix Figure E45Olanzapine vs. placebo – withdrawal – lack of efficacy

Appendix Figure E46Olanzapine vs. placebo – withdrawal – adverse events

Appendix Figure E47Olanzapine vs. placebo – serious adverse events

Appendix Figure E48Olanzapine vs. placebo – EPS

Appendix Figure E49Olanzapine vs. placebo – emergent depression

Appendix Figure E50Olanzapine vs. placebo – weight gain

Appendix Figure E51Olanzapine vs. lithium – response

Appendix Figure E52Olanzapine vs. lithium – overall withdrawal

Appendix Figure E53Olanzapine vs. lithium – withdrawal – adverse events

Appendix Figure E54Olanzapine vs. divalproex/valproate – response

Appendix Figure E55Olanzapine vs. divalproex/valproate – remission

Appendix Figure E56Olanzapine vs. divalproex/valproate – YMRS

Appendix Figure E57Olanzapine vs. divalproex/valproate – CGI

Appendix Figure E58Olanzapine vs. divalproex/valproate – overall withdrawal

Appendix Figure E59Olanzapine vs. divalproex/valproate – withdrawal - lack of efficacy

Appendix Figure E60Olanzapine vs. divalproex/valproate – withdrawal - adverse events

Appendix Figure E61Olanzapine vs. divalproex/valproate – SAE

Appendix Table E23Outcomes summary table: olanzapine versus placebo for acute mania

Drug	Study PMID RoB	Responder/Remitter	Symptom	Function	Other	AE
Olanzapine	Katagiri, 2012²⁰ 22134043 Moderate	See forest plot E40 above for response.	See forest plot E42 above for YMRS.	See forest plot E43 above for CGI.	See forest plot E44, E45, E46 above for Withdrawals.	See forest plots E47, E48, E49, E50 above for Adeverse Effects.
	McIntyre, 2010⁸ 20096936 High	See forest plot E40 above for response.	See forest plot E42 above for YMRS.	See forest plot E43 above for CGI.	See forest plot E44, E45, E46 above for Withdrawals.	See forest plots E41, E42, E43, E44 above for Adeverse Effects.
	McIntyre, 2009⁹ 19839993 High	See forest plot E40 above for response.	See forest plot E42 above for YMRS.	See forest plot E43 above for CGI.	See forest plot E44, E45, E46 above for Withdrawals.	See forest plots E47, E48, E49, E50 above for Adeverse Effects.
	Tohen, 2008b²⁸ 19014751	See forest plot E40 above for response.	See forest plot E42 above for YMRS.	See forest plot E43 above for CGI.	See forest plot E44, E45, E46 above for Withdrawals.	See forest plots E47, E48, E49, E50 above for Adeverse Effects. Suicidal Ideation Olanzapine: 1 case Placebo: 0 cases
	Tohen, 2000²⁹ 10986547 High	See forest plot E40 above for response.	See forest plot E42 above for YMRS.	See forest plot E43 above for CGI.	See forest plot E44, E45, E46 above for Withdrawals.	See forest plots E47, E48, E49, E50 above for Adeverse Effects.

: Abbreviations: AE=Adverse Events; ANCOVA=Analysis of Covariance; CGI=Clinical Global Impressions Scale; CI=Confidence Interval; EPS=extrapyramidal symptoms; ESRS=Extrapyrimidal Symptom Rating Scale; GAS=Global Assessment Scale; MADRS=Montgomery-Asberg Depression Rating Scale; NR=Not reported; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; ROB=Risk of Bias; SAE=Serious Adverse Events; YMRS = Young Mania Rating Scale

Appendix Table E24Strength of evidence assessment: olanzapine versus placebo for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Olanzapine vs. placebo	Response 3 wks	5 RCTs (n=1199)	Favors Olanzapine OR 1.99 (95% CI 1.29, 3.08)	Moderate	Consistent	Direct	Imprecise	Low
	Remission 3 wks	5 RCTs (n=1199)	Favors Olanzapine OR 1.75 (95% CI 1.19, 2.58)	Moderate	Consistent	Direct	Imprecise	Low
	YMRS 3 wks	5 RCTs (n=1199)	Favors Olanzapine MD 4.9 (95% CI 2.34, 7.45)	Moderate	Consistent	Direct	Imprecise	Low
	CGI-BP-S 3 wks	3 RCTs (n=611)	NS	Moderate	Consistent	Direct	Imprecise	Low
	Withdrawal – Lack of Efficacy, Overall	5 RCTs (n=1199)	Favors Olanzapine	Moderate	Consistent	Direct	Imprecise	Low
	Withdrawal – AE	5 RCTs (n=1199)	NS	Moderate	Consistent	Indirect	Imprecise	Insufficient

: Abbreviations: CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; NS=not significant; RCT=randomized controlled trial; YMRS = Young Mania Rating Scale
: Notes:
1: Publication bias for antipsychotics, antidepressants, and behavioral interventions for depressive disorders is suspected.
2: Data were generally imprecise due to missing data from high attrition rates, which was commonly dealt with by Last Observation Carried Forward (LOCF). LOCF requires an assumption that the health status of patients who dropped out of the trial would not have changed had future observations been recorded, a strong assumption in the context of bipolar disorder research.

Appendix Table E25Outcomes summary: olanzapine versus active comparator for acute mania

Comparison	Study PMID RoB	Responder/Remitter	Symptom	Function	Other	AE
Olanzapine vs. Haloperidol	Tohen, 2003²⁶ 14662554 Moderate Shi, 2002²⁷ 12177585 High	Response 6 weeks NS Olanzapine=169/234 Haloperidol=163/219 P=0.67 12 weeks NS Olanzapine=226/234 Haloperidol=206/219 P=0.42 Remission 6 weeks NS OR = 1.27 (95% CI 0.88, 1.84) P=0.15 12 weeks NS 1.37 (95% CI 0.94, 1.99) P=0.08	YMRS 6 weeks Favors Haloperidol Difference in Difference=−2.2 (95% CI −4.2, −0.2) p=0.03 12 weeks NS Difference in Difference=−0.3 (95% CI −2.0, 1.4) p=0.72	NR	Overall Withdrawal 12 weeks NS Olanzapine=94/234 Haloperidol=103/219 p=0.15 Withdrawal due to Aes 12 weeks NS Olanzapine=19/234 Haloperidol=25/219 p=0.27 Withdrawal, Lack of Efficacy 12 weeks NS Olanzapine=35/234 Haloperidol=33/219	Normalized Weight Change 12 weeks Favors Olanzapine Olanzapine=94/229 Haloperidol=34/211 p<0.001 Emergent Depression 12 weeks NS p=0.10 Akathisia 12 weeks Favors Haloperidol p<0.001
Olanzapine vs. Lithium	Niufan, 2008²² 17531327 Low	See forest plot above Remission 4 weeks Olanzapine=57/69 Lithium=50/71	YMRS 4 weeks Difference in Difference (SE)=−4.5 (1.8) p=0.013 Favors Olanzapine CGI-BP 4 weeks Difference in Difference (SE)=−0.6 (0.2) p=0.009 Favors Olanzapine MADRS 4 weeks Difference in Difference (SE)=-NS	NR	See forest plot above	Severe Harms 4 weeks NS Olanzapine=0/69 Lithium=0/71 EP Symptoms 4 weeks NS Olanzapine=1/69 Lithium=2/71 Normalized Weight Change 4 weeks NS Olanzapine=11/69 Lithium=2/71 Emergent Mood Episodes 4 weeks NS Olanzapine=0/69 Lithium=0/71
	Shafti, 2010³³ 19740546 Moderate	See forest plot above	YMRS 3 weeks Favors Lithium Frequency, Difference in Difference= −12.7 (95% CI −19.0, −6.4) P<0.001 Intensity, Difference in Difference= −8.0 (95% CI −13.9, −2.1) P=0.009 CGI, Severity of Illness 3 weeks NS Difference in Difference= −0.1	NR	See forest plot above	NR
	Berk, 1999³⁰ 10565800 High	NR	Mania Scale 4 weeks NS Difference in Difference=3.1 P=0.32 CGI-BP 4 weeks Favors Olanzapine Difference in Difference=0.5 P=0.03	NR	See forest plot above Withdrawal, Lack of Efficacy 4 weeks NS Olanzapine=1/15 Lithium=0/15	NR
Olanzapine vs. Risperidone	Perlis, 2006²⁴ 17196055 High	Response 3 weeks NS OR = 1.12 (95% CI 0.72, 1.75) P = 0.65 Remission 3 weeks NS OR = 1.57 (95% CI 1.0, 2.51) P = 0.06	YMRS 3 weeks NS Olanzapine=−15.0 Risperidone=−16.6	CGI-BP 3 weeks NS Olanzapine=−1.6 Risperidone=−1.5	Overall Withdrawal 3 weeks Favors Risperidone Olanzapine=35/165 Risperidone=54/164 OR = 0.55 (95% CI 0.33, 0.90) P = 0.019 Withdrawal due to Aes 3 weeks NS Olanzapine=9/165 Risperidone=14/164 OR = 0.62 (95% CI 0.25, 1.48) P = 0.29 Withdrawal, Lack of Efficacy 3 weeks NS Olanzapine=7/165 Risperidone=7/164	EP Symptoms 3 weeks NS Olanzapine=23/165 Risperidone=37/164 P=0.06 Emergent Depression 3 weeks Olanzapine=2/165 Akathisia 3 weeks NS Olanzapine=13/165 Risperidone=17/164 P=0.45 Suicidality 3 weeks 3 patients in the Risperidone arm were discontinued for suicidality
Olanzapine vs. Divalproex/Valproate	Xu, 2015¹⁹ 26060401 Low	NR	YMRS % decrease 4 weeks Olanzapine 75.2 (15.08) Valproate 55.11 (5.72) Favors Olanzapine p<0.01	NR	See forest plot above	See forest plot above
	Tohen, 2008²³ 19014751 Low	See forest plot above	See forest plot above	NR	See forest plot above	Normalized Weight Change 4 weeks Olanzapine=13/202 Divalproex=5/188 Suicide Ideation 3 weeks NS Olanzapine=1/215 Divalproex=0/201 12 weeks NS Olanzapine=2/215 Divalproex=1/201 Weight gain >7% Favored Divalproex p=0.002
	Zajecka, 2002³⁵ 12523875 Revicki, 2003²⁵ 12716270 Moderate	NR	See forest plot above YMRS 4 weeks Favors Olanzapine % Reduction (SD) Olanzapine: 75.2% (15.1%) Divalproex: 55.2% (5.7%) P<0.001	NR	See forest plot above	See forest plot above Emergent Depression 4 weeks NS Olanzapine: 1/57 Divalproex: 1/63 Deaths 4 weeks 1 Olanzapine-treated patient died from diabetic ketoacidosis
	Tohen, 2002²⁸ 12042191 High	See forest plot above	See forest plot above	NR	See forest plot above	See forest plot above EPS No difference between groups

: Abbreviations: AE=Adverse Events; ANCOVA=Analysis of Covariance; CGI=Clinical Global Impressions Scale; CI=Confidence Interval; EPS=extrapyramidal symptoms; ESRS=Extrapyrimidal Symptom Rating Scale; GAS=Global Assessment Scale; MADRS=Montgomery-Asberg Depression Rating Scale; NR=Not reported; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; ROB=Risk of Bias; SAE=Serious Adverse Events; YMRS = Young Mania Rating Scale

Appendix Table E26Strength of evidence assessment: olanzapine versus active comparator for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Olanzapine vs. haloperidol	Response 6,12 wks Remission 6,12 wks YMRS 6, 12 wks Withdrawals	1 RCT (n=453)	See table above	Moderate	Unknown	Direct	Imprecise	Insufficient
Olanzapine vs. Lithium	Response 4 wks	2 RCTs (n=180)	See forest plot above	Moderate	Inconsistent	Direct	Imprecise	Insufficient
Olanzapine vs. Lithium	YMRS 4 wks CGI 4 wks Withdrawal	3 RCT (n=210)	See table above	Moderate	Inconsistent	Direct	Imprecise	Insufficient
Olanzapine vs. Risperidone	Response 3 wk Remission 3 wk YMRS 3 wk CGI Withdrawals	1 RCT (n=329)	See table above	High	Unknown	Direct	Imprecise	Insufficient
Olanzapine vs. Divalproex/Valproate	Response Remission	2 RCTs (n=635)	NS	Moderate	Consistent	Direct	Imprecise	Low
	YMRS	3 RCTs (n=750)	NS	Moderate	Consistent	Direct	Imprecise	Low
	CGI	3 RCTs (n=578)	NS	Moderate	Consistent	Direct	Imprecise	Low
	Withdrawals	4 RCTs (n=867)	NS	Moderate	Consistent	Direct	Imprecise	Low

: Abbreviations: CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; NS=not significant; RCT=randomized controlled trial; YMRS = Young Mania Rating Scale
: Notes:
1: Publication bias for antipsychotics, antidepressants, and behavioral interventions for depressive disorders is suspected.
2: Data were generally imprecise due to missing data from high attrition rates, which was commonly dealt with by Last Observation Carried Forward (LOCF). LOCF requires an assumption that the health status of patients who dropped out of the trial would not have changed had future observations been recorded, a strong assumption in the context of bipolar disorder research.

Section 6. Quetiapine for Acute Mania

Appendix Table E27Characteristics of eligible studies: quetiapine for acute mania

Study, Year Design Location Funder Risk of Bias PMID	# Randomized Age (mean) Sex (% Female) Race (% White) Diagnosis (% BP-I, II, NOS) Setting	Inclusions Key Exclusions	Intervention Dosage	Comparison Dosage	Follow-up Duration	Outcomes Reported Withdrawal (%) at endpoint
Cutler, 2011³⁶ RCT Multisite US Industry RoB Low 22054797	N = 316 Mean Age 41 Female 40% White 47% BP-I 100% Inpatient (days 1–4, minimum) Outpatient (at inspectors discretion)	Mania; YMRS ≥ 20 overall, YMRS ≥ 4 on at least 2 of 4 specifed mania domains, and CGI-BP-S ≥ 4 First Manic Episode Schizoaffective Substance Abuse Other Mental Health Labs/Other Conditions	Quetiapine ER 300–800 mg/day (603.8 mg/day mean)	Placebo	3 Weeks	CGI-BP-S CGI-BP-C MADRS Remission (YMRS≤12) Response (YMRS 50% decrease) YMRS Withdrawal 29%
McElroy, 2010³⁷ Singlesite US Industry RoB Low 19963274	N = 41 Mean Age 35 Female 51% White 69% BP-I 74% BP-II 21% BP-NOS 5% Outpatient	Mild to moderate hypomania or mild mania; CGI-BP ≥3 AND <5 Substance Abuse Other Mental Health Neurological Disorders Pregnant Nursing Labs/Other Conditions	Quetiapine 50–800 mg/day (232 mg/day mean)	Placebo	8 weeks	CGI-BP-S GAF HAM-A IDS Remission (YMRS ≤7 at week 8, CGI-BP Overall ≤2 at week 8, Improvement or no change in IDS score from baseline to week 8) Response (YMRS 50% decrease) YMRS Withdrawal 36%
Vieta, 2010¹⁸ RCT Multisite 3 continents Industry RoB High 20565430	N = 493 Mean Age 39 Female 42% Race NR BP-I 100% Inpatient (1 week) Outpatient (weeks 2–3, subject to inspector discretion)	Mania; YMRS ≥ 20 First Manic Episode Schizoaffective Substance Abuse Neurological Disorders	Quetiapine 400–800 mg/day (600 mg/day mean)	Placebo (Palidperidone arm discussed in Other Drugs section)	3 weeks	Duration of Episode YMRS GAF PANSS CGI-BP-S SAS AIMS MADRS Withdrawal 28%
Li, 2008³⁸ RCT Multisite China Industry RoB Moderate 18028587	N = 154 Mean Age 33 Female 53% Race NR Diagnosis NR Inpatient (weeks 1–2) Outpatient (week 2–4, subject to inspector discretion)	Mania; YMRS ≥ 20 Substance Abuse Taking Other Meds Pregnant/Nursing Labs/Other Conditions	Quetiapine 100–800 mg/day (648.2 mg/day mean)	Lithium 250–2000 mg/day (target serum level 0.6–1.2 mmol/L) (0.80 mmol/L average)	4 weeks	MADRS PANSS Remission (various definitions) Response (YMRS 50% decrease) Weight YMRS Withdrawal 12%
Bowden, 2005³⁹ RCT Multisite 2 Continents Industry RoB High 15669897	N = 302 Mean Age 39 Female 24% Race NR BP-I 100% Inpatient	Mania; YMRS ≥ 20 including score of at least 4 on 2 of the 4 double-weighted items (irritability, speech, content, and disruptive/aggressive behavior), CGI ≥4 First Manic Episode Substance Abuse Taking Other Meds Pregnant/Nursing Labs/Other Conditions	Quetiapine 100–800mg/day	Placebo Lithium 0.6–1.4 mEq/L (mean 0.80 mEq/L)	12 weeks	CGI-BP-S Overall Global Assessment Scale (GAS) MADRS PANSS (positive) Remission (YMRS≤12) Response (50% decrease in YMRS) YMRS Withdrawal 48%

: Abbreviations: AIMS=Abnormal Involuntary Movement Scale; BARS=Barnes Akathisia Scale; BAS=Behavioral Approach System; BMI=Body Mass Index; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; C=comparison; CGI= Clinical Global Impressions; CGI-I=Clinical Global Impressions-Improvement; CGI-S =CGI-Severity; CGI-BP=Clinical Global Impressions Scale-Bipolar; CGI-BP-C= Clinical Global Impressions, Bipolar, Change Scale; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; C-SSRS=Columbia Suicide Severity Rating Scale; DAI-10=Drug Attitutde Inventory, 10 question version; DIEPSS=Drug-Induced Extra-Pyramidal Symptoms Scale; DSM=Diagnostic and Statistical Manual of Mental Disorders; EPS=extrapyramidal symptoms; ER=Extended Release; ESRS=Extrapyramidal Symptom Rating Scale; GAF=General Assessment of Functioning Scale; GAS=Global Assessment Scale; HAM-A=Hamilton Scale for Anxiety; HAM-D=Hamilton Scale for Depression; HRQL=Health-related quality of life; HRQOL=Health-related quality of life; I=intervention; IDS=Inventory for Depressive Symptoms; LIFE= Longitudinal Interval Follow-up Evaluation; MADRS=Montgomery-Asberg Depression Rating Scale; MAS=Bech-Rafaelsen Mania Rating Scale; MRS=Mania Rating Scale; MSRS=Manic state rating scale; NOS=not otherwise specified; NR=not reported; PANSS=Positive and Negative Syndrome Scale; PRS=Polygenic Risk Scores; PGWB=Psychological General Well-Being Index; PMID=PubMed Identification Number; PRS=Polygenic Risk Scores; Q-LES-Q=Quality of Life Enjoyment and Satisfaction Questionnaire; RCT=randomized controlled trial; ROB=risk of bias; SADS-C= Schedule for Affective Disorders and Schizophrenia-Change version; SAE=Serious Adverse Events; SAS=Simpson Angus Scale; SF-12=12-Item Short Form Health Survey; SF-36=36-Item Short Form Health Survey; SLICE=Streamlined Longitudinal Interview Clinical Evaluation; T=Trial; YMRS = Young Mania Rating Scale

Appendix Table E28Summary risk of bias assessments: quetiapine for acute mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Quetiapine	McElroy, 2010³⁷ Industry 19963274	Moderate	No specific sources of bias identified. Attrition rate 36%
	Cutler, 2011³⁶ Industry 22054797	Low	Blinding not described. No other sources of bias identified.
	Vieta, 2010¹⁸ Industry 20565430	High	Blinding not described; large dropout in placebo group (41%).
	Li, 2008³⁸ Industry 18028587	Moderate	Randomization and blinding procedure not described.
	Bowden, 2005³⁹ Industry 15669897	High	Randomization and blinding procedure not described; >50% dropout in placebo group at day 84; 33% at 3 weeks
	McIntyre, 2005¹⁴ Industry 16139175	Moderate	Dropout rate for quetiapine and placebo in 30%–40% range, lacks some core information on how allocation was concealed and blinding of treatment staff and raters was maintained. Author notes may be underpowered for quetiapine vs. haloperidol comparison.

: Abbreviations: ITT=Intention to Treat; PMID=PubMed Identification Number; LOCF=last observation carried forward

Quetiapine Forest Plots

Appendix Figure E62Quetiapine vs. placebo – response

Appendix Figure E63Quetiapine vs. placebo – remission

Appendix Figure E64Quetiapine vs. placebo – YMRS

Appendix Figure E65Quetiapine vs. placebo – CGI

Appendix Figure E66Quetiapine vs. placebo – overall withdrawal

Appendix Figure E67Quetiapine vs. placebo – withdrawal lack of efficacy

Appendix Figure E68Quetiapine vs. placebo – withdrawal adverse events

Appendix Table E29Outcomes summary: quetiapine versus placebo for acute mania

Drug	Study PMID RoB	Responder/Remitter	Symptom	Function	Other	AE
Quetiapine	McElroy, 2010³⁷ 19963274 Moderate	Response 8 weeks Completers only reported Remission 8 weeks Completers only reported	YMRS 8 weeks Regression model NS (p=0.06)	CGI 8 weeks Regression model Favors Quetiapine (p<0.001) GAF 8 weeks Regression model NS	Overall Withdrawal Quetiapine 6/21 Placebo 8/20 Withdrawal Lack of efficacy Quetiapine 0/21 Placebo 2/20 Withdrawal AE Quetiapine 2/21 Placebo 1/20	Serious Adverse Events 3 weeks 3 placebo – 2 suicide, 1 death, 1 quetiapine – suicide attempt Deaths 3 weeks 1 placebo EPS 3 weeks 3.8% placebo 6.6% Quetiapine
	Cutler, 2011³⁶ 22054797 Low	See forest plot E62 above for Response.	See forest plot E64 above for YMRS.	See forest plot E65 above for CGI	See forest plots E66, E67, E68 above for withdrawals	SAE Quetiapine 4.0% Placebo 8.1% Deaths 3 placebo – 2 suicide, 1 death, 1 quetiapine – suicide attempt EPS 3 weeks 3.8% placebo 6.6% Quetiapine
	Vieta, 2010¹⁸ 20565430 High	See forest plot E562 above for Response.	See forest plot E64 above for YMRS.	See forest plot E65 above for CGI	See forest plots E66, E67, E68 above for withdrawals	SAE Reported no difference 1 suicide reported Akathisia Quetiapine 6 (3%) Placebo 3 (3%)
	Bowden, 2005³⁹ 15669897 High	See forest plot E62 above for Response.	See forest plot E64 above for YMRS.	See forest plot E65 above for CGI	See forest plots E66, E67, E68 above for withdrawals	SAE None reported EPS Reported no difference Weight gain >7% Quetiapine more frequent (p=0.008)
	McIntyre, 2005¹⁴ 16139175 Moderate	See forest plot E62 above for Response.	YMRS 3 weeks ANCOVA model Favors Quetiapine p=.01 Results sustained at 12 weeks	CGI 3 weeks ANCOVA model Favors Quetiapine (p<0.05) Results sustained at 12 weeks	See forest plots E66, E67, E68 above for withdrawals	SAE None reported EPS Quetiapine 13 (12.7%) Placebo 16 (15.8%) NS Weight gain >7% Quetiapine 12.8% Placebo 4% NS

: Abbreviations: AE=Adverse Events; ANCOVA=Analysis of Covariance; CGI=Clinical Global Impressions Scale; CI=Confidence Interval; EPS=extrapyramidal symptoms; ESRS=Extrapyrimidal Symptom Rating Scale; GAS=Global Assessment Scale; MADRS=Montgomery-Asberg Depression Rating Scale; NR=Not reported; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; ROB=Risk of Bias; SAE=Serious Adverse Events; YMRS = Young Mania Rating Scale

Appendix Table E30Strength of evidence assessment: quetiapine versus placebo for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Quetiapine vs. placebo	Response 3 wks	4 RCT (n=1,007)	Favors Quetiapine OR 2.07 (95% CI 1.39, 3.09)	Moderate	Consistent	Direct	Imprecise	Low
	Remission 3 wks	3 RCT (n=699)	NS	High	Consistent	Direct	Imprecise	Insufficient
	YRMS 3 wks	5 RCT (n=699 forest plot, 1439 total)	Favors Quetiapine MD 4.92 (95% CI 0.31, 9.53)	Moderate	Inconsistent	Direct	Imprecise	Low
	CGI-BP-S 3 wk	5 RCT (n=806 forest plot, 1439 total)	Favors Quetiapine Mean Difference 0.54 (95% CI 0.35, 0.74)	Moderate	Consistent	Direct	Imprecise	Low
	Withdrawal – AE, Overall	4 RCT (n=1,007)	NS	Moderate	Consistent	Indirect	Imprecise	Insufficient
	Withdrawal –Lack of Efficacy	4 RCT (n=1,007)	Favors Quetiapine Mean Difference 0.38 (95% CI 0.23, 0.63)	Moderate	Consistent	Direct	Imprecise	Low

: Abbreviations: CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; NS=not significant; RCT=randomized controlled trial; YMRS = Young Mania Rating Scale
: Notes:
1: Publication bias for antipsychotics, antidepressants, and behavioral interventions for depressive disorders is suspected.
2: Data were generally imprecise due to missing data from high attrition rates, which was commonly dealt with by Last Observation Carried Forward (LOCF). LOCF requires an assumption that the health status of patients who dropped out of the trial would not have changed had future observations been recorded, a strong assumption in the context of bipolar disorder research.

Appendix Table E31Outcomes summary: quetiapine versus active comparator for acute mania

Comparison	Study PMID RoB	Responder/Remitter	Symptom	Function	Other	AE
Quetiapine vs. haloperidol	McIntyre, 2005¹⁶ 16139175 Moderate	Response 3 weeks Quetiapine 42.6% Haloperidol 56.1% NS Remission 3 weeks Quetiapine 27.7% Haloperidol 36.7% NS	YMRS Change 3 week Quetiapine −12.29 Haloperidol −15.71 No Statistical Tests reported	CGI-BP-S Change 3 week Quetiapine −1.02 Haloperidol −1.33 No Statistical Tests reported GAS 12 weeks Favors quetiapine against placebo p < .001 12 weeks Favors haloperidol against placebo p < .001	NR Overall Withdrawal Quetiapine 55/102 Haloperidol 45/99 Withdrawal Lack of Efficacy Quetiapine 18/102 Haloperidol 10/99 Withdrawal AE Quetiapine 5/102 Haloperidol 10/99	Serious Adverse Events 12 weeks 0 in both arms Deaths 12 weeks 0 in both arms EPS 12 weeks 12.7% Quetiapine 59.6% Haloperidol
Quetiapine vs. lithium	Bowden, 2005 15669897	Response 12 weeks Quetiapine 72.0% Lithium 75.5% No Statistical Tests reported Remission 12 weeks Quetiapine 69.2% Lithium 72.4% No Statistical Tests reported	YMRS Change 12 weeks Quetiapine −20.28 Lithium −20.76 NS	CGI-BP-S Change 12 weeks Quetiapine −2.20 Lithium −2.18 No Statistical Tests reported GAS Change 12 weeks Quetiapine 26.35 Lithium NR No Statistical Tests reported	NR	Serious Adverse Events 12 weeks 0 in both arms Deaths 12 weeks 0 in both arms EPS 12 weeks 9.3% placebo 13.1% Quetiapine NR Lithium
	Li, 2008 18028587 Moderate	Response 4 weeks Favors quetiapine Quetiapine 77.9% Lithium 59.7% p=0.013 Remission 4 weeks Favors quetiapine Quetiapine 70.1% Lithium 48.1% p=0.007	YMRS Change 4 weeks Quetiapine −18.2 (10.4) Lithium −15.9 (12.2) NS	NR	NR	Serious Adverse Events 4 weeks 0 in both arms Deaths 4 weeks 0 in both arms EPS 4 weeks 5.1% Quetiapine 6.5% lithium

: Abbreviations: AE=Adverse Events; ANCOVA=Analysis of Covariance; CGI=Clinical Global Impressions Scale; CI=Confidence Interval; EPS=extrapyramidal symptoms; ESRS=Extrapyrimidal Symptom Rating Scale; GAS=Global Assessment Scale; MADRS=Montgomery-Asberg Depression Rating Scale; NR=Not reported; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; ROB=Risk of Bias; SAE=Serious Adverse Events; YMRS = Young Mania Rating Scale

Appendix Table E32Strength of evidence assessment: quetiapine versus active comparator for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Quetiapine vs. haloperidol	Response Remission YMRS CGI Withdrawals	1 RCT (n=199)	See table above	Moderate	Unknown	Direct	Imprecise	Insufficient
Quetiapine vs. lihtium	Response Remission YMRS Withdrawals	2 RCTs (n=456)	See table	High	Inconsistent	Direct	Imprecise	Insufficient

: Abbreviations: CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; NS=not significant; RCT=randomized controlled trial; YMRS = Young Mania Rating Scale
: Notes:
1: Publication bias for antipsychotics, antidepressants, and behavioral interventions for depressive disorders is suspected.
2: Data were generally imprecise due to missing data from high attrition rates, which was commonly dealt with by Last Observation Carried Forward (LOCF). LOCF requires an assumption that the health status of patients who dropped out of the trial would not have changed had future observations been recorded, a strong assumption in the context of bipolar disorder research.

Section 7. Risperidone for Acute Mania

Appendix Table E33Characteristics of eligible studies: Risperidone for acute mania

Study, Year Design Location Funder Risk of Bias PMID	# Randomized Age (mean) Sex (% Female) Race (% White) Diagnosis (% BP-I, II, NOS) Setting	Inclusions Key Exclusions	Intervention Dosage	Comparison Dosage	Follow-up Duration	Outcomes Reported Withdrawal (%) at endpoint
Smulevich, 200515 RCT Multisite 2 Continents Industry RoB Moderate 15572276	N = 438 Mean Age 40 Female 47% White 65% BP-I 100% Inpatient	Mania; YMRS ≥ 20 and MADRS ≤ 20 First Manic Episode Schizoaffective Substance Abuse Other Mental Health Taking Other Meds	Risperidone 1–6 mg/day (mean 4.2 mg/day)	C1: Placebo C2: Haloperidol 2–12 mg/day (mean 8.0 mg/day)	12 weeks (12 week outcomes excluded due to attrition	BPRS CGI-S GAS MADRS YMRS Withdrawal 48% at 12 weeks 12% at 3 weeks
Khanna, 200540 RCT Multisite India Industry RoB Moderate 16135859	N = 290 Mean Age 35 Female 38% Race NR BP-I 100% Inpatient	Mania; YMRS ≥ 20 Schizoaffective Substance Abuse Other Mental Health Taking Other Meds	Risperidone 1–6 mg/day	Placebo	3 weeks	CGI-S MADRS PANSS YMRS Withdrawal 20%
Segal, 199841 RCT Singlesite South Africa Industry/University RoB Moderate 9617509	N = 45 Mean Age 34 Female 78% Race NR BP-I 100% Inpatient	Mania; DSM-IV criteria for Bipolar Manic Phase Substance Abuse Taking Other Meds Pregnant/Nursing Labs/Other Conditions	Risperidone 6 mg/day	C1: Placebo C2: Haloperidol 10 mg/day C3: Lithium 0.6–1.2 mmol/L	4 weeks	BPRS CGI Unknown Scale - Not reported whether global improvement or severity scale is being reported GAF MRS Seclusion - Hours of eclusion - Proportion of patients needing SAS Withdrawal NR

: Abbreviations: AIMS=Abnormal Involuntary Movement Scale; BARS=Barnes Akathisia Scale; BAS=Behavioral Approach System; BMI=Body Mass Index; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; C=comparison; CGI= Clinical Global Impressions; CGI-I=Clinical Global Impressions-Improvement; CGI-S =CGI-Severity; CGI-BP=Clinical Global Impressions Scale-Bipolar; CGI-BP-C= Clinical Global Impressions, Bipolar, Change Scale; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; C-SSRS=Columbia Suicide Severity Rating Scale; DAI-10=Drug Attitutde Inventory, 10 question version; DIEPSS=Drug-Induced Extra-Pyramidal Symptoms Scale; DSM=Diagnostic and Statistical Manual of Mental Disorders; EPS=extrapyramidal symptoms; ER=Extended Release; ESRS=Extrapyramidal Symptom Rating Scale; GAF=General Assessment of Functioning Scale; GAS=Global Assessment Scale; HAM-A=Hamilton Scale for Anxiety; HAM-D=Hamilton Scale for Depression; HRQL=Health-related quality of life; HRQOL=Health-related quality of life; I=intervention; IDS=Inventory for Depressive Symptoms; LIFE= Longitudinal Interval Follow-up Evaluation; MADRS=Montgomery-Asberg Depression Rating Scale; MAS=Bech-Rafaelsen Mania Rating Scale; MRS=Mania Rating Scale; MSRS=Manic state rating scale; NOS=not otherwise specified; NR=not reported; PANSS=Positive and Negative Syndrome Scale; PRS=Polygenic Risk Scores; PGWB=Psychological General Well-Being Index; PMID=PubMed Identification Number; PRS=Polygenic Risk Scores; Q-LES-Q=Quality of Life Enjoyment and Satisfaction Questionnaire; RCT=randomized controlled trial; ROB=risk of bias; SADS-C= Schedule for Affective Disorders and Schizophrenia-Change version; SAE=Serious Adverse Events; SAS=Simpson Angus Scale; SF-12=12-Item Short Form Health Survey; SF-36=36-Item Short Form Health Survey; SLICE=Streamlined Longitudinal Interview Clinical Evaluation; T=Trial; YMRS = Young Mania Rating Scale

Appendix Table E34Summary risk of bias assessments: risperidone for acute mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Risperidone	Smulevich, 2005¹⁵ Industry 15572276	Moderate	Randomization and blinding procedures not well-described. Some participants treated in open-label fashion. 12% dropout.
	Khanna, 2005⁴⁰ Industry 16135859	Moderate	Randomization and blinding procedures not described. Handling of data from missing persons not described. 20% dropout.
	Segal, 1998⁴¹ Industry/University 9617509	Moderate	Randomization not described, patients assigned consecutively which infers both a lack of randomization and a likelihood of a lack of allocation concealment.

: Abbreviations: ITT=Intention to Treat; PMID=PubMed Identification Number; LOCF=last observation carried forward

Risperidone Forest Plots

Appendix Figure E69Risperidone vs. placebo – response

Appendix Figure E70Risperidone vs. placebo – YMRS

Appendix Figure E71Risperidone vs. placebo – CGI

Appendix Figure E72Risperidone vs. placebo – overall withdrawal

Appendix Figure E73Risperidone vs. placebo – withdrawal – adverse events

Appendix Table E35Outcomes summary: risperidone versus placebo for acute mania

Drug	Study PMID RoB	Responder/Remitter	Symptom	Function	Other	AE
Risperidone	Khanna, 2005⁴⁰ 16135859 Moderate	See forest plot E69 above for Response	See forest plot E70 above for YMRS MADRS 3 weeks Mean change Risperidone: −3.2 (0.4) Placebo: −2.5, (0.34) P<0.001)	See forest plot E70 above for CGI	See forest plot E72, E73 above for Withdrawal	Serious Adverse Events 3 weeks 0 in both arms Deaths 3 weeks 0 in both arms EPS 3 weeks 6.0% placebo 36.0% Risperidone
Risperidone	Smulevich, 2005¹⁵ 15572276 Moderate	See forest plot E69 above for Response	See forest plot E70 above for YMRS	See forest plot E70 above for CGI GAS 3 week Risperidone −17.1(1.8) Placebo −10.3(1.7) No Statistical Tests reported	See forest plot E72, E73 above for Withdrawal	No reported SAE EPS Mean ESRS score increases greater for haloperidol than risperidone (p<0.001)

: Abbreviations: AE=Adverse Events; ANCOVA=Analysis of Covariance; CGI=Clinical Global Impressions Scale; CI=Confidence Interval; EPS=extrapyramidal symptoms; ESRS=Extrapyrimidal Symptom Rating Scale; GAS=Global Assessment Scale; MADRS=Montgomery-Asberg Depression Rating Scale; NR=Not reported; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; ROB=Risk of Bias; SAE=Serious Adverse Events; YMRS = Young Mania Rating Scale

Appendix Table E36Strength of evidence assessment: risperidone versus placebo for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Risperidone vs. placebo	Response 3 wks YMRS 3 wks CGI 3 wks	2 RCTs (n=584)	Favors Risperidone	Moderate	Consistent	Direct	Imprecise	Low

: Abbreviations: CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; NS=not significant; RCT=randomized controlled trial; YMRS = Young Mania Rating Scale
: Notes:
1: Publication bias for antipsychotics, antidepressants, and behavioral interventions for depressive disorders is suspected.
2: Data were generally imprecise due to missing data from high attrition rates, which was commonly dealt with by Last Observation Carried Forward (LOCF). LOCF requires an assumption that the health status of patients who dropped out of the trial would not have changed had future observations been recorded, a strong assumption in the context of bipolar disorder research.

Appendix Table E37Outcomes summary: risperidone versus active comparator for acute mania

Drub	Study PMID RoB	Responder/Remitter	Symptom	Function	Other	AE
Risperidone vs. haloperidol	Smulevich, 2005¹⁵ 15572276 Moderate	Response 3 weeks Risperidone 48% Haloperidol 47% NS	YMRS Change 3 week Risperidone −15.1(10.3) Haloperidol −13.9(10.3) NS	CGI-S Change 3 week Risperidone −1.4(1.2) Haloperidol −1.3(1.1) NS GAS 3 week Risperidone −17.1(1.8) Haloperidol −13.9(10.3) NS	Withdrawal lack of efficacy Risperidone 4% Haloperidol 3% Withdrawal adverse events Risperidone 3% Haloperidol 1%	Serious Adverse Events 12 weeks 0 in both arms Deaths 12 weeks 0 in both arms EPS NR
Risperidone vs. haloperidol	Segal, 1998⁴¹ 9617509 Moderate	NR	MRS 4 weeks NS	CGI 4 weeks NS GAF 4 weeks NS	NR	Serious Adverse Events 4 weeks 0 in both arms Deaths 4 weeks 0 in both arms EPS NR

: Abbreviations: AE=Adverse Events; CI=Confindence Interval; CGI=Clinical Global Impressions Scale; CGI-BP=Clinical Global Impressions Scale, Bipolar; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S=Clinical Global Impressions; Severity Scale; EPS=extrapyramidal symptoms; GAF=Global Assessment of Functioning Scale; GAS=Global Assessment Scale; MADRS=Montgomery-Asberg Syndrome Scale; MRS=Mania Rating Scale; NR=not reported; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; RoB=Risk of Bias; SD=Standard Deviation; SE=standard error; YMRS = Young Mania Rating Scale

Appendix Table E38Strength of evidence assessment: risperidone versus active comparator for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Risperidone vs. haloperidol	Response 3 wks YMRS 3 wks CGI-S 3 wks	2 RCTs (n=438)	See table above	Moderate	Consistent	Direct	Imprecise	Insufficient
Risperidone vs. lithium	YMRS 4 wks CGI 4 wks GAF 4 wks	1 RCT (n=45)	See table above	Moderate	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; NS=not significant; RCT=randomized controlled trial; YMRS = Young Mania Rating Scale
: Notes:
1: Publication bias for antipsychotics, antidepressants, and behavioral interventions for depressive disorders is suspected.
2: Data were generally imprecise due to missing data from high attrition rates, which was commonly dealt with by Last Observation Carried Forward (LOCF). LOCF requires an assumption that the health status of patients who dropped out of the trial would not have changed had future observations been recorded, a strong assumption in the context of bipolar disorder research.

Section 8. Ziprasidone for Acute Mania

Appendix Table E39Characteristics of eligible studies: ziprasidone drug treatments for acute mania by year then first author

Study, Year Design Location Funder Risk of Bias PMID	# Randomized Age (mean) Sex (% Female) Race (% White) Diagnosis (% BP-I, II, NOS) Setting	Inclusions Key Exclusions	Intervention Dosage	Comparison Dosage	Follow-up Duration	Outcomes Reported Withdrawal (%) at endpoint
Potkin, 200542 RCT Multisite 2 Continents Industry RoB Low 16012271	N = 206 Mean Age 40 Female 49% White 62% BP-I 100% Inpatient	Mania; Mania Rating Scale (SADS-C interview derived; Spitzer, 1978) ≥14 with score ≥2 on four items at screening and admission Schizoaffective Substance Abuse Other Mental Health Taking Other Meds Pregnant/Nursing	Ziprasidone 80-160 mg/day (112 mg/day mean)	Placebo	3 weeks	BMI or Weight CGI-I CGI-S GAF HAM-D MADRS MRS PANSS Withdrawal 41%
Keck, 200343 RCT Multisite 2 Continents Industry RoB Moderate 12668364	N = 210 Mean Age 38 Female 46% Race NR BP-I 100% Inpatient	Mania; Mania Rating Scale (SADS-C interview derived; Spitzer, 1978) ≥14 with score ≥2 on four items at screening and admission Schizoaffective Substance Abuse Other Mental Health Taking Other Meds Pregnant/Nursing Labs/Other Conditions	Ziprasidone 40-80 mg bid (mean ≈130 mg/day)	Placebo	3 weeks	MRS CGI-S CGI-I PANSS GAF Adverse Events AIMS Withdrawal 50%

: Abbreviations: AIMS=Abnormal Involuntary Movement Scale; BARS=Barnes Akathisia Scale; BAS=Behavioral Approach System; BMI=Body Mass Index; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; C=comparison; CGI= Clinical Global Impressions; CGI-I=Clinical Global Impressions-Improvement; CGI-S =CGI-Severity; CGI-BP=Clinical Global Impressions Scale-Bipolar; CGI-BP-C= Clinical Global Impressions, Bipolar, Change Scale; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; C-SSRS=Columbia Suicide Severity Rating Scale; DAI-10=Drug Attitutde Inventory, 10 question version; DIEPSS=Drug-Induced Extra-Pyramidal Symptoms Scale; DSM=Diagnostic and Statistical Manual of Mental Disorders; EPS=extrapyramidal symptoms; ER=Extended Release; ESRS=Extrapyramidal Symptom Rating Scale; GAF=General Assessment of Functioning Scale; GAS=Global Assessment Scale; HAM-A=Hamilton Scale for Anxiety; HAM-D=Hamilton Scale for Depression; HRQL=Health-related quality of life; HRQOL=Health-related quality of life; I=intervention; IDS=Inventory for Depressive Symptoms; LIFE= Longitudinal Interval Follow-up Evaluation; MADRS=Montgomery-Asberg Depression Rating Scale; MAS=Bech-Rafaelsen Mania Rating Scale; MRS=Mania Rating Scale; MSRS=Manic state rating scale; NOS=not otherwise specified; NR=not reported; PANSS=Positive and Negative Syndrome Scale; PRS=Polygenic Risk Scores; PGWB=Psychological General Well-Being Index; PMID=PubMed Identification Number; PRS=Polygenic Risk Scores; Q-LES-Q=Quality of Life Enjoyment and Satisfaction Questionnaire; RCT=randomized controlled trial; ROB=risk of bias; SADS-C= Schedule for Affective Disorders and Schizophrenia-Change version; SAE=Serious Adverse Events; SAS=Simpson Angus Scale; SF-12=12-Item Short Form Health Survey; SF-36=36-Item Short Form Health Survey; SLICE=Streamlined Longitudinal Interview Clinical Evaluation; T=Trial; YMRS = Young Mania Rating Scale

Appendix Table E40Summary risk of bias assessments: ziprasidone for acute mania by year then first author

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Ziprasidone	Keck, 2003⁴³ Industry 12668364	Moderate	All core sources of bias appear to have been addressed, however, almost 50% dropout.
Ziprasidone	Potkin, 2005⁴² Industry 16012271	Low	No sources of bias identified. Well disclosed and reported study.

: Abbreviations: ITT=Intention to Treat; PMID=PubMed Identification Number; LOCF=last observation carried forward

Ziprasidone Forest Plots

Appendix Figure E74Ziprasidone vs. placebo – response

Appendix Figure E75Ziprasidone vs. placebo – CGI

Appendix Figure E76Ziprasidone vs. placebo – overall withdrawal

Appendix Figure E77Ziprasidone vs. placebo – withdrawal – lack of efficacy

Appendix Figure E78Ziprasidone vs. placebo – withdrawal – adverse events

Appendix Table E41Outcomes summary: ziprasidone versus placebo for acute mania

Drug	Study PMID RoB	Responder/Remitter	Symptom	Function	Other	AE
Ziprasidone	Keck, 2003⁴³ 12668364 Moderate	See forest plot E74 above for Response	See forest plot above	See forest plot E75 above for CGI GAF 3 weeks F=10.35, df=1, 156, p<0.005 Favors intervention	See forest plots 76, 77, and 78 above	Serious Adverse Events 3 weeks 0 in both arms Deaths 3 weeks 0 in both arms EPS NR
Ziprasidone	Potkin, 2005⁴² 16012271 Moderate	See forest plot E74 above for Response	See forest plot above	See forest plot E75 above for CGI GAF 3 weeks Favors intervention p ≤.001 No statistical test reported	See plots 76, 77, and 78 above	Serious Adverse Events 3 weeks 1 Ziprasidone Deaths 3 weeks 1 Ziprasidone – Suicide EPS 3 weeks 1.5% placebo 10.8% Ziprasidone

: Abbreviations: AE=Adverse Events; ANCOVA=Analysis of Covariance; CGI=Clinical Global Impressions Scale; CI=Confidence Interval; EPS=extrapyramidal symptoms; ESRS=Extrapyrimidal Symptom Rating Scale; GAS=Global Assessment Scale; MADRS=Montgomery-Asberg Depression Rating Scale; NR=Not reported; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; ROB=Risk of Bias; SAE=Serious Adverse Events; YMRS = Young Mania Rating Scale

Appendix Table E42Strength of evidence assessment: ziprasidone versus placebo for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Ziprasidone vs. placebo	Response 3 wks YMRS 3 wks CGI 3 wks	2 RCTs (n=402)	Favors Ziprasidone	Moderate	Consistent	Direct	Imprecise	Low

: Abbreviations: CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; NS=not significant; RCT=randomized controlled trial; YMRS = Young Mania Rating Scale
: Notes:
1: Publication bias for antipsychotics, antidepressants, and behavioral interventions for depressive disorders is suspected.
2: Data were generally imprecise due to missing data from high attrition rates, which was commonly dealt with by Last Observation Carried Forward (LOCF). LOCF requires an assumption that the health status of patients who dropped out of the trial would not have changed had future observations been recorded, a strong assumption in the context of bipolar disorder research.

Section 9. Aripiprazole Plus Mood Stabilizer

Appendix Table E43Characteristics of eligible studies: aripiprazole plus mood stabilizer drug treatments for acute mania

Study, Year Design Location Funder Risk of Bias PMID	# Randomized Age (mean) Sex (% Female) Race (% White) Diagnosis (% BP I, II, NOS) Setting	Inclusions Key Exclusions	Intervention Dosage	Comparison Dosage	Follow-up Duration	Outcomes Reported Withdrawal (%) at endpoint
NCT00665366 2013 Unpublished RCT Multiste 3 Continents Industry RoB NA	N = 370 Mean Age 45 Female 54% White 95% BP I 100% Setting NR	Mania, manic or mixed episode, with or without psychotic features Schizoaffective Substance Abuse Other Mental Health Neurological disorders Pregnant/Nursing Labs/Other Conditions	Aripiprazole 5-15 mg/day Adjunctive to valproate or lithium	Placebo Adjunctive to valproate or lithium	12 weeks	Response (≥50% YMRS decrease) Remission (YMRS ≤ 12) YMRS CGI-BP FAST LIFE-RIFT PGI-I Weight change Withdrawal 32%
Jeong, 2012⁴⁴ RCT Multisite South Korea Industry 22592508 RoB Low	N = 42 Mean Age 37 Female 64% Race NR BP I 100% Inpatient	Manic; DSM-IV-TR criteria YMRS ≥20 Schizoaffective Substance Abuse Other Mental Health Taking Other Meds Labs/Other Conditions	Aripiprazole Flexible dosing Mean 20 mg/day Adjunctive to valproic acid (serum level 50-125 mg/mL)	Haloperidol Flexible dosing Mean 5 mg/day Adjunctive to valproic acid (serum level 50-125 mg/mL)	8 weeks	Response (≥50% YMRS decrease) Remission (YMRS ≤ 12) YMRS CGI-S Drug-induced Extrapyramidal Symptoms Scale Weight gain Withdrawal 7%
Vieta, 2008⁴⁵ RCT Multisite/Not Disclosed Industry RoB Moderate 18381903	N = 384 Mean Age 42 Female 54% White 91% BP I 100% Outpatient	Manic/Mixed episode; Partial responders to Lithium or Valproate; YMRS≥16 with decrease of ≤25% after 6 weeks of stabilization treatment Substance Abuse Other Mental Health	Aripiprazole 15-30 mg/day (19.0 mg/day) Adjunctive to lithium/divalproex/valproate	Placebo Adjunctive to lithium/divalproex/valproate	6 weeks	YMRS Response Adverse Events EPS CGI-BP Withdrawal 19%

: Abbreviations: AIMS=Abnormal Involuntary Movement Scale; ASI=Addiction Severity Index; BAS=Behavioral Approach System; BID=Twice a day; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; C=Comparison; CGI-BP=Clinical Global Impressions Scale, Bipolar; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-I= Clinical Global Impressions-Improvement; CGI-S== Clinical Global Impressions-Severity Scale; DSM-IV-TR= Diagnostic and statistical manual, 4^th edition, Text Revision; EPS=extrapyramidal symptoms; FAST=Functional Assessment Short Test; GAF=General Assessment of Functioning Scale; GAS= Global Assessment Scale; HAM-D=Hamilton Scale for Depression; HAMD-21=Hamilton Rating Scale for Depression (21-items); HDRS-21=Hamilton Depression Rating Scale (21=items); ISST=International Suicide Prevention Trial Scale for Suicidal Thinking; LIFE-RIFT=Longitudinal Interval Follow-up Evaluation-Rating Impaired Functioning Tool; MADRS=Montgomery-Asberg Depression Rating Scale; NOS=not otherwise specified; NR=not reported; OR=Odds Ratio; PANSS=Positive and Negative Syndrome Scale; PAS=Premornid Adjustment Scale; PGI-I=Patient Global Impression Improvement; PMID=PubMed Identification Number; QLS=Quality of Life Scale; RCT=randomized controlled trial; RDQ=Readiness to Discharge Questionnaire; ROB=risk of bias; SANS=Scale for the Assessment of Negative Symptoms; SAPS=Scale for the Assessment of Positive Symptoms; SAS=Simpson Angus Scale; SF-36=36-Item Short Form Health Survey; UKU=UKU rating scale; YMRS = Young Mania Rating Scale

Appendix Table E44Summary risk of bias assessments: arirprizaole plus mood stabilizers for acute mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Aripiprazole	Jeong, 2012⁴⁴ Industry 22592508	Low	May be underpowered and raters may not be blinded. 7% dropout.
Aripiprazole	Vieta 2008⁴⁵ Industry 18381903	Moderate	Randomization and blinding procedures not disclosed.

: Abbreviations: ITT=intention to treat; PMID=PubMed Identification Number

Antipsychotics Plus Mood Stabilizer Forest Plots

Appendix Figure E79Adjunctive aripiprazole vs. placebo – 3 week response

Appendix Figure E80Adjunctive aripiprazole vs. placebo – last response

Appendix Figure E81Adjunctive aripiprazole vs. placebo – 3 week remission

Appendix Figure E82Adjunctive aripiprazole vs. placebo – last remission

Appendix Figure E83Adjunctive aripiprazole vs. placebo – YMRS

Appendix Figure E84Adjunctive aripiprazole vs. placebo – CGI

Appendix Figure E85Adjunctive aripiprazole vs. placebo – overall withdrawal

Appendix Figure E86Adjunctive aripiprazole vs. placebo – withdrawal – lack of efficacy

Appendix Figure E87Adjunctive aripiprazole vs. placebo – withdrawal – adverse events

Appendix Figure E88Adjunctive aripiprazole vs. placebo – serious adverse events

Appendix Figure E89Adjunctive aripiprazole vs. placebo – akasthisia

Appendix Figure E90Adjunctive aripiprazole vs. placebo – akasthisia

Appendix Table E45Outcomes summary: aripiprazole plus mood stabilizers versus placebo for acute mania

Drug	Study PMID RoB	Responder/Remitter	Symptom	Function	Other	AE
Aripiprazole adjunctive vs. placebo	NCT00665366 2013	See forest plots E79, E80, E81, and E82 above.	See forest plot E83 above.	See forest plot E84 above for CGI	See forest plot E85, E86 and E87 above for Withdrawals.	See forest plot E88, E89, and E90 above for adverse events. Very Serious AE 1 reported case of suicide ideation related to depression in the aripiprazole arm 1 case of acute respiratory failure in the Aripiprazole arm Cases of Severe Depression 12 weeks NS Aripiprazole = 4/180 Placebo= 2/189 OR = 2.05 (0.37, 16.72) ; P = 0.38 Cases of Manic Reaction or Relapse 12 weeks NS Aripiprazole = 2/180 Placebo= 7/189 OR = 0.31 (0.04, 1.34) ; P = 0.18
Aripiprazole adjunctive vs. placebo	Vieta, 2008⁴⁵ 18381903 Moderate	See forest plots E79, E80, E81, and E82 above.	See forest plot E83 above.	NR	See forest plot E85, E86 and E87 above for Withdrawals.	See forest plot above. EPS 6 weeks Favors Placebo Aripiprazole =71/253 Placebo=18/130 OR = 2.41 (1.39, 4.37) ; P = 0.002 Normalized Weight Change (> 7% change) 6 weeks NS Aripiprazole = 7/253 Placebo= 5/130 OR = 0.71 (0.22, 2.50) ; P = 0.57 Cases of Psychiatric Disorder 6 weeks NS Aripiprazole = 6/253 Placebo= 3/130 OR = 1.00 (0.25, 5.11) ; P = 0.97

: Abbreviations: AE=Adverse Events; ASI=Addiction Severity Index; BPRS=Brief Psychiatric Rating Scale; CGI-Bp=Clinical Global Impresions Scale for Bipolar Disorder; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S=Clinical Global Impressions, Severity Scale; CI=Confidence Interval; EPS=extrapyramidal symptoms; GAF=General Assessment of Functioning Scale; HAM-D=Hamilton Scale for Depression; MADRS=Montgomery-Asberg Syndrome Scale; NR=not reported; NS=not significant; OR=Odds Ratio; PAS=Premorbid Adjustment Scale; PMID=PubMed Identification Number; QLS=Quality of Life Scale; ROB=risk of bias; SAE=Serious Adverse Events; SE=Standard Error; UKU=UKU rating scale;YMRS = Young Mania Rating Scale

Appendix Table E46Strength of evidence assessment: aripiprazole plus mood stabilizers versus placebo for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Aripiprazole adjunctive vs. placebo	Response 6 wks Remission 6 wks YMRS 6 wks CGI-BP 6 wks Withdrawals	2 RCTs (n=752)	See forest plots	High	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; NS=not significant; RCT=randomized controlled trial; YMRS = Young Mania Rating Scale
: Notes:
1: Publication bias for antipsychotics, antidepressants, and behavioral interventions for depressive disorders is suspected.
2: Data were generally imprecise due to missing data from high attrition rates, which was commonly dealt with by Last Observation Carried Forward (LOCF). LOCF requires an assumption that the health status of patients who dropped out of the trial would not have changed had future observations been recorded, a strong assumption in the context of bipolar disorder research.

Appendix Table E47Outcomes summary: aripipirazole plus mood stabilizers versus active comparison for acute mania

Drug	Study PMID	Responder/Remitter	Symptom	Function	Other	AE
Aripiprazole adjunctive vs. haloperidol adjunctive	Jeong, 2012⁴⁴ 22592508 RoB	Response 3 weeks NS Aripiprazole= 20 (71.4%) Haloperidol= 11 (78.6%) No statistical test reported 8 weeks NS Aripiprazole=24 (85.7%) Haloperidol= 13 (92.9%) No statistical test reported Remission 3 weeks NS Aripiprazole= 18 (64.3%) Haloperidol= 9 (64.3%) No statistical test reported 8 weeks NS Aripiprazole= 23 (82.1%) Haloperidol= 12 (85.7%) No statistical test reported	Change in YMRS 8 weeks NS Change (SE) Aripiprazole= −16.3 (1.6) Haloperidol= −17.5 (2.3) P=0.66	Change in CGI-BP 8 weeks NS Change (SE) Aripiprazole= 2.0 (0.2) Haloperidol= 1.7 (0.3) P=0.41	Overall Withdrawal 8 weeks NS Aripiprazole = 2 (7.1%) Haloperidol = 1 (7.1%) No statistical test reported Withdrawal due to Lack of Efficacy 8 weeks NS Aripiprazole =1 (3.6%) Haloperidol =0 (0%) No statistical test reported Withdrawal due to AEs 8 weeks NS Aripiprazole = 1 (3.6%) Haloperidol = 1 (7.1%) No statistical test reported	Extrapyramidal Symptoms 8 weeks Favors Aripiprazole Aripiprazole =32.1% Haloperidol =50% No statistical test reported Normalized Weight Change (>7% change) 8 weeks Favors Comparator Aripiprazole =18/28 Haloperidol =4/14 P=0.049 Emergent Mood Episode (Depression) 8 weeks Aripiprazole =2/28 Haloperidol =3/14 No statistical test reported Akathisia 8 weeks Aripiprazole =7/28 Haloperidol =2/14 No statistical test reported

: Abbreviations: AE=Adverse Events; CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; CGI-BP-S-Clinical Global Impressions, Bipolar, Severity Scale; HAMD= Hamilton Scale for Depression; NS=not significant; PMID=PubMed Identification Number; ROB=risk of bias; SAE; Serious Adverse Events; SE=standard error; YMRS = Young Mania Rating Scale

Appendix Table E48Strength of evidence assessment: aripiprazole plus mood stabilizers versus active comparison for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Aripiprazole adjunctive vs. haloperidol adjunctive	3 weeks Response Remission YMRS CGI-BP Withdrawal – overall Withdrawal – lack of efficacy Withdrawal – Aes	1 RCT (n=42)	See table above	Low	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; NS=not significant; RCT=randomized controlled trial; YMRS = Young Mania Rating Scale
: Notes:
1: Publication bias for antipsychotics, antidepressants, and behavioral interventions for depressive disorders is suspected.
2: Data were generally imprecise due to missing data from high attrition rates, which was commonly dealt with by Last Observation Carried Forward (LOCF). LOCF requires an assumption that the health status of patients who dropped out of the trial would not have changed had future observations been recorded, a strong assumption in the context of bipolar disorder research.

Section 10. Asenapine Plus Mood Stabilizer

Appendix Table E49Characteristics of eligible studies: asenapine plus mood stabilizer drug treatments for acute mania

Study, Year Design Location Funder Risk of Bias PMID	# Randomized Age (mean) Sex (% Female) Race (% White) Diagnosis (% BP I, II, NOS) Setting	Inclusions Key Exclusions	Intervention Dosage	Comparison Dosage	Follow-up Duration	Outcomes Reported Withdrawal (%) at endpoint
Szegedi, 2012⁴⁶ RCT Multisite 4 Continents Industry RoB Moderate 22198448	N = 324 Mean Age 39 Female 43% White 57% BP I 100% Outpatient	Mania; YMRS ≥ 20 Current episode ≤3 months Substance Abuse Other Mental Health Neurological Disorders Taking Other Meds Pregnant/Nursing Labs/Other Conditions First Manic Episode	Asenapine 5-10 mg BID (Mean 11.8 mg/day) Adjunctive to Lithium 0.6-1.2 mmol/L (mean 12.8 mg/day) OR Valproate 50-125 mcg/mL (mean 11.0 mg/day)	Placebo Adjunctive to Lithium 0.6-1.2 mmol/L (mean 12.8 mg/day) OR Valproate 50-125 mcg/mL (mean 11.0 mg/day)	3 weeks (12 week >50% attrition)	YMRS MADRS CGI-BP ISST SF-36 RDQ Adverse Events Withdrawal 37%

: Abbreviations: AIMS=Abnormal Involuntary Movement Scale; ASI=Addiction Severity Index; BAS=Behavioral Approach System; BID=Twice a day; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; C=Comparison; CGI-BP=Clinical Global Impressions Scale, Bipolar; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-I= Clinical Global Impressions-Improvement; CGI-S== Clinical Global Impressions-Severity Scale; DSM-IV-TR= Diagnostic and statistical manual, 4^th edition, Text Revision; EPS=extrapyramidal symptoms; FAST=Functional Assessment Short Test; GAF=General Assessment of Functioning Scale; GAS= Global Assessment Scale; HAM-D=Hamilton Scale for Depression; HAMD-21=Hamilton Rating Scale for Depression (21-items); HDRS-21=Hamilton Depression Rating Scale (21=items); ISST=International Suicide Prevention Trial Scale for Suicidal Thinking; LIFE-RIFT=Longitudinal Interval Follow-up Evaluation-Rating Impaired Functioning Tool; MADRS=Montgomery-Asberg Depression Rating Scale; NOS=not otherwise specified; NR=not reported; OR=Odds Ratio; PANSS=Positive and Negative Syndrome Scale; PAS=Premornid Adjustment Scale; PGI-I=Patient Global Impression Improvement; PMID=PubMed Identification Number; QLS=Quality of Life Scale; RCT=randomized controlled trial; RDQ=Readiness to Discharge Questionnaire; ROB=risk of bias; SANS=Scale for the Assessment of Negative Symptoms; SAPS=Scale for the Assessment of Positive Symptoms; SAS=Simpson Angus Scale; SF-36=36-Item Short Form Health Survey; UKU=UKU rating scale; YMRS = Young Mania Rating Scale

Appendix Table E50Summary risk of bias assessments: asenapine plus mood stabilizers for acute mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Asenapine	Szegedi, 2012⁴⁶ Industry 22198448	Moderate (3 week outcomes)	Statistically significant difference in the number of patients who complete the trial for both arms, but ‘if patients who had recurrence were also counted as completers, then completion rates were 73.3% for olanzapine and 67.3% for lithium’ -- which are similar but dropout rates are still moderately high (30%).

: Abbreviations: ITT=intention to treat; PMID=PubMed Identification Number

Appendix Table E51Outcomes summary: asenapine plus mood stabilizers versus placebo for acute mania

Drug	Study PMID RoB	Responder/Remitter	Symptom	Function	Other	AE
Asenapine adjunctive vs. placebo	Szegedi, 2012⁴⁶ 22198448 Moderate	Response No difference between groups OR 1.14 (0.71, 1.84) Remission No difference between groups OR 1.47 90.90, 2.42)	YRMS Favors asenapine Mean difference 2.03 (0.26, 3.80)	CGI-BP-S Favors asenapine Mean difference 0.30 (0.08, 0.52)	NR at 3 weeks	Serious Adverse Events 52 weeks 1 Asenapine Deaths 52 weeks 1 Asenapine – suicide EPS 52 weeks 12% placebo 9.5% Asenapine

: Abbreviations: AE=Adverse Events; ASI=Addiction Severity Index; BPRS=Brief Psychiatric Rating Scale; CGI-Bp=Clinical Global Impresions Scale for Bipolar Disorder; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S=Clinical Global Impressions, Severity Scale; CI=Confidence Interval; EPS=extrapyramidal symptoms; GAF=General Assessment of Functioning Scale; HAM-D=Hamilton Scale for Depression; MADRS=Montgomery-Asberg Syndrome Scale; NR=not reported; NS=not significant; OR=Odds Ratio; PAS=Premorbid Adjustment Scale; PMID=PubMed Identification Number; QLS=Quality of Life Scale; ROB=risk of bias; SAE=Serious Adverse Events; SE=Standard Error; UKU=UKU rating scale;YMRS = Young Mania Rating Scale

Appendix Table E52Strength of evidence assessment: asenapine plus mood stabilizers versus placebo for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Asenapine adjunctive vs. placebo	Response 3 wks YMRS 3 wks CGI-BP 3 wks	1 RCT (n=324)	NS	Moderate	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; NS=not significant; RCT=randomized controlled trial; YMRS = Young Mania Rating Scale
: Notes:
1: Publication bias for antipsychotics, antidepressants, and behavioral interventions for depressive disorders is suspected.
2: Data were generally imprecise due to missing data from high attrition rates, which was commonly dealt with by Last Observation Carried Forward (LOCF). LOCF requires an assumption that the health status of patients who dropped out of the trial would not have changed had future observations been recorded, a strong assumption in the context of bipolar disorder research.

Section 11. Olanzapine Plus Mood Stabilizer

Appendix Table E53Characteristics of eligible studies: olanzapine plus mood stabilizer drug treatments for acute mania

Study, Year Design Location Funder Risk of Bias PMID	# Randomized Age (mean) Sex (% Female) Race (% White) Diagnosis (% BP I, II, NOS) Setting	Inclusions Key Exclusions	Intervention Dosage	Comparison Dosage	Follow-up Duration	Outcomes Reported Withdrawal (%) at endpoint
Conus, 2015⁴⁷ RCT Single-site Australia Industry RoB Low 26485297	N = 83 Mean Age 22 Female 32% Race NR BP I 100% Inpatient	First manic or mixed episode; YMRS ≥20 Other Mental Health Neurological Disorders Taking Other Meds Pregnant/Nursing Labs/Other Conditions	Olanzapine 5 mg/day adjusted by 2.5 mg/day Adjunctive to lithium 500 mg/day increased by 500 mg/twice daily	Chlorpromazine 100 mg/day adjusted by 50-100 mg/day Adjunctive to lithium 500 mg/day increased by 500 mg/twice daily	8 weeks	Response (≥ 50% YMRS reduction) Remission (YMRS ≤ 12) Symptomatic recovery (YMRS ≤ 12 and HAMD-21 < 7) Efficacy YMRS CGI-BP BPRS HAMD-21 SAPS SANS ASI PAS GAF QLS Adverse events UKU Withdrawal 14%
Xu, 2015¹⁹ RCT Single-site China Government RoB Low 26060401	N = 120 Mean Age 31 Female 52% Race NR BP 1 100% Setting NR	First manic; YMRS ≥17 Substance Abuse Neurological Disorders Taking Other Meds Pregnant/Nursing	Olanzapine 10 mg/day + Valproate 600 mg/day	C1: Olanzapine 10 mg/day Flexible dosing 5-20 mg/day C2: Valproate 600 mg/day alone	4 weeks	Efficacy YMRS CGI-BP Adverse events Extrapyramidal symptoms SAS Withdrawal 5%
Houston, 2009⁴⁸ RCT US and Puerto Rico Industry RoB High 19778495	N = 202 Mean Age 39 Female 59% White 51% BP I 100% Outpatient	Mixed Episode; YMRS ≥ 16 HDRS-21 (inadequate response to divalproex) First Manic Episode Taking Other Meds Labs/Other Conditions	Olanzapine 5-20 mg/day Adjunctive to divalproex (adjusted for blood levels between 75-125 µg/mL)	Divalproex alone (adjusted for blood levels between 75-125 µg/mL)	6 weeks	Response (≥ 50% decrease HDRS-21 and ≥ 25% decrease YMRS) Remission (YMRS ≤ 12 and HDRS-21 ≤ 8) Efficacy HDRS-21 YMRS CGI-BP Adverse events Extrapyramidal symptoms Withdrawal 42%
Tohen, 2008a⁴⁹ RCT Multisite 3 Continents Industry RoB Moderate 18245032	N = 118 Mean Age 41 Female 58% Race NR BP I 100% Inpatient and Outpatient	Manic or Mixed Episode; YMRS ≥20 Labs/Other Conditions	Olanzapine 10-30 mg/day Adjunctive to carbamazepine 400-1200 mg/day	Placebo Adjunctive to carbamazepine 400-1200 mg/day	6 weeks blinded (26 weeks open-label extension)	Efficacy YMRS CGI (multiple subscales) MADRS Adverse events Extrapyramidal symptoms SAS BAS AIMS Withdrawal 28% at 6 weeks
Tohen, 2002a⁵⁰ RCT Multisite US and Canada Industry RoB High 11779284 15337326⁵¹ 15572737⁵²	N = 344 Mean Age 41 Female 52% White 85% Diagnosis NR Outpatient	Manic or Mixed Episode; YMRS ≥ 16 First Manic Episode Labs/Other Conditions	Olanzapine 10 mg/day with flexible dosing from 5-20 mg/day Adjunctive to ongoing open-label valproate or lithium	Placebo Adjunctive to ongoing open-label valproate or lithium	6 weeks	Efficacy YMRS HAM-D PANSS CGI Remission Adverse Events Extrapyramidal symptom Withdrawal 30%

: Abbreviations: AIMS=Abnormal Involuntary Movement Scale; ASI=Addiction Severity Index; BAS=Behavioral Approach System; BID=Twice a day; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; C=Comparison; CGI-BP=Clinical Global Impressions Scale, Bipolar; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-I= Clinical Global Impressions-Improvement; CGI-S== Clinical Global Impressions-Severity Scale; DSM-IV-TR= Diagnostic and statistical manual, 4^th edition, Text Revision; EPS=extrapyramidal symptoms; FAST=Functional Assessment Short Test; GAF=General Assessment of Functioning Scale; GAS= Global Assessment Scale; HAM-D=Hamilton Scale for Depression; HAMD-21=Hamilton Rating Scale for Depression (21-items); HDRS-21=Hamilton Depression Rating Scale (21=items); ISST=International Suicide Prevention Trial Scale for Suicidal Thinking; LIFE-RIFT=Longitudinal Interval Follow-up Evaluation-Rating Impaired Functioning Tool; MADRS=Montgomery-Asberg Depression Rating Scale; NOS=not otherwise specified; NR=not reported; OR=Odds Ratio; PANSS=Positive and Negative Syndrome Scale; PAS=Premornid Adjustment Scale; PGI-I=Patient Global Impression Improvement; PMID=PubMed Identification Number; QLS=Quality of Life Scale; RCT=randomized controlled trial; RDQ=Readiness to Discharge Questionnaire; ROB=risk of bias; SANS=Scale for the Assessment of Negative Symptoms; SAPS=Scale for the Assessment of Positive Symptoms; SAS=Simpson Angus Scale; SF-36=36-Item Short Form Health Survey; UKU=UKU rating scale; YMRS = Young Mania Rating Scale

Appendix Table E54Summary risk of bias assessments: olanzapine plus mood stabilizers for acute mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Olanzapine	Conus, 201547 Industry 26485297	Low	Physician and patients may not be blinded. Dropout balanced and accounted for in analysis.
	Xu, 201519 Government 26060401	Low	Well-constructed, described, and reported study. 5% dropout.
	Houston, 200948 Industry 19778495	High	Randomization and blinding procedures not described. 42% dropout.
	Tohen, 2008a49 Industry 18245032	Moderate	Blinding procedure not described. 28% dropout.
	Tohen, 2002a50 Industry 11779284	High	Randomization and blinding procedures not described. 30% dropout.

: Abbreviations: ITT=intention to treat; PMID=PubMed Identification Number

Antipsychotics Plus Mood Stabilizer Forest Plots

Appendix Figure E91Adjunctive olanzapine vs. placebo – response

Appendix Figure E92Adjunctive olanzapine vs. placebo – remission

Appendix Figure E93Adjunctive olanzapine vs. placebo – YMRS

Appendix Figure E94Adjunctive olanzapine vs. placebo – CGI

Appendix Figure E95Adjunctive olanzapine vs. placebo – overall withdrawal

Appendix Figure E96Adjunctive olanzapine vs. placebo – withdrawal – lack of efficacy

Appendix Figure E97Adjunctive olanzapine vs. placebo – withdrawal – adverse events

Appendix Figure E98Adjunctive olanzapine vs. placebo – serious adverse events

Appendix Figure E99Adjunctive olanzapine vs. placebo – emergent depression last

Appendix Figure E100Adjunctive olanzapine vs. placebo – weight

Appendix Table E55Outcomes summary: olanzapine plus mood stabilizers versus placebo for acute mania

Drug	Study PMID RoB	Responder/Remitter	Symptom	Function	Other	AE
Olanzapine adjunctive vs. chlorpromazine	Conus, 2015⁴⁷ 26485297 Low	Symptomatic Recovery 8 weeks Olanzapine=53.3% Chlorpromazine=54.5% P=0.56 Response 8 weeks Olanzapine=96.7% Chlorpromazine=84.8% P=0.12	YMRS 8 weeks Score ≤12 Olanzapine=93.3% Chlorpromazine=72.7% P=0.03 Favors intervention HAMD-21 8 weeks Score <7 Olanzapine=53.3% Chlorpromazine=63.6% P=0.28 NS	GAF 8 weeks NS No statistical test reported QLS 8 weeks NS No statistical test reported PAS 8 weeks NS No statistical test reported CGI-BP 8 weeks NS No statistical test reported	ASI 8 weeks NS No statistical test reported Weight Gain 8 weeks NS; p=0.22 Overall Withdrawal 8 weeks Olanzapine=4/42 Chlorpromazine=5/41 NS	UKU 8 weeks NS No statistical test reported AE Leading to Trial Medication Interruption 8 weeks Olanzapine=5.3% Chlorpromazine=6.8% NS P=0.47
Olanzapine adjunctive vs. placebo or no placebo	Xu, 2015¹⁹ 26060401 Low	NR	YMRS 3 weeks Favors Olanzapine % Reduction (SD) Olanzapine+Valporate=86.5% (8.9%) Valproate=55.2% (5.7%) P<0.01 CGI-BP 3 weeks Difference in Difference (SE) 1.4 (0.53) Favors Olanzapine p<0.01	NR	Overall Withdrawal 3 weeks NS Olanzapine+Valporate=2/40 Valproate=3/40 Withdrawal due to AEs 3 weeks NS Olanzapine+Valporate=2/40 Valproate=0/40 Withdrawal, Lack of Efficacy 3 weeks NS Olanzapine+Valporate=0/40 Valproate=2/40	Severe Harms 3 weeks NS Olanzapine+Valporate=1/38 Valproate=0/37 Normalized Weight Change 3 weeks Olanzapine+Valporate=31/38 Valproate=21/37 Emergent Mood Episodes 3 weeks NS Olanzapine+Valporate=0/38 Valproate=0/37
	Houston, 2009⁴⁸ 19778495 High	See forest plots E91 and E92 above	YMRS See forest plot E93 above	CGI-BP See forest plot E94 above	See forest plots E95, E96 and E97 above	SAE See forest plot E98 above Deaths 1 fatality from a car accident in the Olanzapine arm Hepatic Failure 1 case of acute hepatic failure in the Olanzapine arm Weight gain See forest plot E100 above
	Tohen, 2008⁴⁹ 18245032 Moderate	See forest plots E91 and E92 above	YMRS See forest plot E93 above MADRS 6 weeks Change (SE) Olanzapine −1.22 (0.96) Placebo −1.00 (0.96) NS	NR	See forest plots E95, E96 and E97 above	SAE See forest plots E98 aboveabove Emergent depression See forest plot E99 above Weight gain See forest plot E100 above
	Tohen, 2002⁵⁰ 11779284 High Baker, 2004⁵² 15572737 High Namijoshi, 2004⁵¹ 15337326 High	See forest plots E91 and E92 above	YMRS See forest plot E93 above	CGI-BP See forest plot E94 above	See forest plots E95, E96 and E97 above	SAE See forest plot E98 above EPS NS Emergent depression See forest plot E99 above

: Abbreviations: AE=Adverse Events; ASI=Addiction Severity Index; BPRS=Brief Psychiatric Rating Scale; CGI-Bp=Clinical Global Impresions Scale for Bipolar Disorder; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S=Clinical Global Impressions, Severity Scale; CI=Confidence Interval; EPS=extrapyramidal symptoms; GAF=General Assessment of Functioning Scale; HAM-D=Hamilton Scale for Depression; MADRS=Montgomery-Asberg Syndrome Scale; NR=not reported; NS=not significant; OR=Odds Ratio; PAS=Premorbid Adjustment Scale; PMID=PubMed Identification Number; QLS=Quality of Life Scale; ROB=risk of bias; SAE=Serious Adverse Events; SE=Standard Error; UKU=UKU rating scale;YMRS = Young Mania Rating Scale

Appendix Table E56Strength of evidence assessment: olanzapine plus mood stabilizers versus placebo for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Olanzapine vs. Placebo/adjunctive to Lithium or Valproate	6 weeks Remission Response YMRS CGI-BP Withdrawals	3 RCTs (n=664)	See table above	High	Consistent	Direct	Imprecise	Insufficient
Olanzapine vs. Placebo/adjunctive to Carbamazepine	Response Remission YMRS CGI-BP Withdrawals	1 RCT (n=118)	See table above	Moderate	Unknown	Direct	Imprecise	Insufficient
Olanzapine vs. No Placebo/adjunctive to Divalproex/Valproate	Response Remission YMRS CGI-BP Withdrawals	1 RCT (n=202)	See table above	High	Unknown	Direct	Imprecise	Insufficient
Olanzapine vs. No Placebo/adjunctive to Valproate	YMRS 3 weeks CGI-BP 3 weeks Withdrawals	1 RCT (n=80)	See table above	Low	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; NS=not significant; RCT=randomized controlled trial; YMRS = Young Mania Rating Scale
: Notes:
1: Publication bias for antipsychotics, antidepressants, and behavioral interventions for depressive disorders is suspected.
2: Data were generally imprecise due to missing data from high attrition rates, which was commonly dealt with by Last Observation Carried Forward (LOCF). LOCF requires an assumption that the health status of patients who dropped out of the trial would not have changed had future observations been recorded, a strong assumption in the context of bipolar disorder research.

Appendix Table E57Outcomes summary: olanzapine plus mood stabilizers versus active comparison for acute mania

Drug	Study PMID	Responder/Remitter	Symptom	Function	Other	AE
Olanzapine adjunctive vs. chlorpromazine adjunctive	Conus, 2015⁴⁷ 26485297 Low	Response 8 weeks Olanzapine 94.7% Chlorpromazine 97.2% NS Remission 8 weeks Olanzapine 89.5% Chlorpromazine 88.9% NS	YMRS 8 weeks NS (data not reported) HAMD 8 weeks NS (data not reported)	CGI-BP-S 8 weeks NS (data not reported)	Withdrawal – Aes Olanzapine 26.3% Chlorpromazine 30.6% NS	SAE 3 chlorpromazine (extrapyramidal symptoms) 2 olanzapine (neutropenia, sedation) Weight gain NS

: Abbreviations: AE=Adverse Events; CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; CGI-BP-S-Clinical Global Impressions, Bipolar, Severity Scale; HAMD= Hamilton Scale for Depression; NS=not significant; PMID=PubMed Identification Number; ROB=risk of bias; SAE; Serious Adverse Events; SE=standard error; YMRS = Young Mania Rating Scale

Appendix Table E58Strength of evidence assessment: olanzapine plus mood stabilizers versus active comparison for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Olanzapine adjunctive vs. chlorpromazine adjunctive	Response Remission YMRS HAMD Withdrawal AE	1 RCT (n=83)	See table above	Low	Unknown	Direct	Imprecise	Iinsufficient

: Abbreviations: CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; NS=not significant; RCT=randomized controlled trial; YMRS = Young Mania Rating Scale
: Notes:
1: Publication bias for antipsychotics, antidepressants, and behavioral interventions for depressive disorders is suspected.
2: Data were generally imprecise due to missing data from high attrition rates, which was commonly dealt with by Last Observation Carried Forward (LOCF). LOCF requires an assumption that the health status of patients who dropped out of the trial would not have changed had future observations been recorded, a strong assumption in the context of bipolar disorder research.

Section 12. Quetiapine Plus Mood Stabilizer

Appendix Table E59Characteristics of eligible studies: quetiapine plus mood stabilizer drug treatments for acute mania by year then first author

Study, Year Design Location Funder Risk of Bias PMID	# Randomized Age (mean) Sex (% Female) Race (% White) Diagnosis (% BP I, II, NOS) Setting	Inclusions Key Exclusions	Intervention Dosage	Comparison Dosage	Follow-up Duration	Outcomes Reported Withdrawal (%) at endpoint
Yatham, 2007⁵³ RCT Multisite 4 Continents Industry RoB High 17519644	N = 200 Mean Age 40 Female 50% Race NR BP I 100% Inpatient (1 week) Outpatient (weeks 2-3, subject to inspector discretion)	Mania; YMRS ≥ 20 AND ≥ 4 on at least 2 YMRS subscales AND CGI-BP-S ≥ 4 First Manic Episode Taking Other Meds Pregnant/Nursing	Quetiapine 100-800 mg/day (455 mg/day mean) Adjunctive to Valproate 50-100 mcg/mL target OR Lithium 0.7-1.0 mEq/L target	Placebo Adjunctive to Valproate 50-100 mcg/mL target OR Lithium 0.7-1.0 mEq/L target	3 weeks	CGI-BP-S Remission (Various definitions) Response (YMRS 50% decrease) YMRS Withdrawal 36%
Yatham, 2004⁵⁴ RCT Multisite 4 Continents Industry RoB Moderate 15538120	N = 402 Mean Age 40 Female 47% Race NR BP I 100% Inpatient	Mania; At least one manic or mixed episode in previous 5 years. YMRS ≥ 20, including score ≥ 4 on two core YMRS items; CGI-BP ≥ 4 First Manic Episode Substance Abuse Other Mental Health Pregnant/Nursing	Quetiapine 100-800 mg/day (492 mg/day mean) Adjunctive to Valproate 50-100 mcg/mL target OR Lithium 0.7-1.0 mEq/L target	Placebo Adjunctive to Valproate 50-100 mcg/mL target OR Lithium 0.7-1.0 mEq/L target	6 weeks	YMRS CGI-BP PANSS MADRS GAS Adverse Events Withdrawals 38%

: Abbreviations: AIMS=Abnormal Involuntary Movement Scale; ASI=Addiction Severity Index; BAS=Behavioral Approach System; BID=Twice a day; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; C=Comparison; CGI-BP=Clinical Global Impressions Scale, Bipolar; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-I= Clinical Global Impressions-Improvement; CGI-S== Clinical Global Impressions-Severity Scale; DSM-IV-TR= Diagnostic and statistical manual, 4^th edition, Text Revision; EPS=extrapyramidal symptoms; FAST=Functional Assessment Short Test; GAF=General Assessment of Functioning Scale; GAS= Global Assessment Scale; HAM-D=Hamilton Scale for Depression; HAMD-21=Hamilton Rating Scale for Depression (21-items); HDRS-21=Hamilton Depression Rating Scale (21=items); ISST=International Suicide Prevention Trial Scale for Suicidal Thinking; LIFE-RIFT=Longitudinal Interval Follow-up Evaluation-Rating Impaired Functioning Tool; MADRS=Montgomery-Asberg Depression Rating Scale; NOS=not otherwise specified; NR=not reported; OR=Odds Ratio; PANSS=Positive and Negative Syndrome Scale; PAS=Premornid Adjustment Scale; PGI-I=Patient Global Impression Improvement; PMID=PubMed Identification Number; QLS=Quality of Life Scale; RCT=randomized controlled trial; RDQ=Readiness to Discharge Questionnaire; ROB=risk of bias; SANS=Scale for the Assessment of Negative Symptoms; SAPS=Scale for the Assessment of Positive Symptoms; SAS=Simpson Angus Scale; SF-36=36-Item Short Form Health Survey; UKU=UKU rating scale; YMRS = Young Mania Rating Scale

Appendix Table E60Summary risk of bias assessments: quetiapine plus mood stabilizers for acute mania by year then first author

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Quetiapine	Yatham, 2007⁵³ Industry 17519644	High	Randomization and blinding not described. Improper definition of ITT “consisted of all the patients who had received at least one dose of study drug and had undergone a baseline AND at least one postbaseline efficacy assessment"; 2 patients missing from baseline quet. Measures, 9 patients missing from baseline placebo measures.
Quetiapine	Yatham, 2004⁵⁴ Industry 15538120	Moderate	Blinding and randomization not described; differential dropout rates between arms may alter effectiveness of randomization

: Abbreviations: ITT=intention to treat; PMID=PubMed Identification Number

Antipsychotics Plus Mood Stabilizer Forest Plots

Appendix Figure E101Adjunctive Quetiapine vs. placebo – response

Appendix Figure E102Adjunctive Quetiapine vs. placebo - remission

Appendix Figure E103Adjunctive Quetiapine vs. placebo – YMRS

Appendix Figure E104Adjunctive Quetiapine vs. placebo – CGI-BP-S

Appendix Figure E105Adjunctive Quetiapine vs. placebo – withdrawal lack of efficacy

Appendix Figure E106Adjunctive Quetiapine vs. placebo – withdrawal adverse events

Appendix Figure E107Adjunctive Quetiapine vs. placebo – overall withdrawal

Appendix Table E61Outcomes summary: quetiapine plus mood stabilizers versus placebo for acute mania

Drug	Study PMID RoB	Responder/Remitter	Symptom	Function	Other	AE
Quetiapine adjunctive vs. placebo	Yatham, 2007⁵³ 17519644 High	See forest plots E101 and E102 above	See forest plot E103 above	See forest plot E104 above	See forest plots E105, E106, and E107 above	Serious Adverse Events 6 weeks 1 placebo Deaths 6 weeks 1 placebo EPS 6 weeks 29.2% placebo 17.9% Quetiapine + Lithium
Quetiapine adjunctive vs. placebo	Yatham, 2004⁵⁴ 15538120 Moderate	See forest plots E101 and E102 above	See forest plot E103 above	See forest plot E104 above	See forest plots E105, E106, and E107 above	Serious Adverse Events 6 weeks 0 in all arms Deaths 6 weeks 0 in all arms EPS 6 weeks 19.2% placebo 21.4% Quetiapine + Lithium

: Abbreviations: AE=Adverse Events; ASI=Addiction Severity Index; BPRS=Brief Psychiatric Rating Scale; CGI-Bp=Clinical Global Impresions Scale for Bipolar Disorder; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S=Clinical Global Impressions, Severity Scale; CI=Confidence Interval; EPS=extrapyramidal symptoms; GAF=General Assessment of Functioning Scale; HAM-D=Hamilton Scale for Depression; MADRS=Montgomery-Asberg Syndrome Scale; NR=not reported; NS=not significant; OR=Odds Ratio; PAS=Premorbid Adjustment Scale; PMID=PubMed Identification Number; QLS=Quality of Life Scale; ROB=risk of bias; SAE=Serious Adverse Events; SE=Standard Error; UKU=UKU rating scale;YMRS = Young Mania Rating Scale

Appendix Table E62Strength of evidence assessment: quetiapine plus mood stabilizers versus placebo for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Quetiapine adjunctive vs. placebo	Response 3 wks Remission 3 wks YMRS 3 wks CGI-BP 3 wks Withdrawals	2 RCTs (n=570)	See forest plots above	High	Consistent	Direct	Imprecise	Insufficient

: Abbreviations: CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; NS=not significant; RCT=randomized controlled trial; YMRS = Young Mania Rating Scale
: Notes:
1: Publication bias for antipsychotics, antidepressants, and behavioral interventions for depressive disorders is suspected.
2: Data were generally imprecise due to missing data from high attrition rates, which was commonly dealt with by Last Observation Carried Forward (LOCF). LOCF requires an assumption that the health status of patients who dropped out of the trial would not have changed had future observations been recorded, a strong assumption in the context of bipolar disorder research.

Section 13. Risperidone Plus Mood Stabilizer

Appendix Table E63Characteristics of eligible studies: risperidone plus mood stabilizer drug treatments for acute mania by year then first author

Study, Year Design Location Funder Risk of Bias PMID	# Randomized Age (mean) Sex (% Female) Race (% White) Diagnosis (% BP I, II, NOS) Setting	Inclusions Key Exclusions	Intervention Dosage	Comparison Dosage	Follow-up Duration	Outcomes Reported Withdrawal (%) at endpoint
Yatham, 2003⁵⁵ RCT Multisite 4 Continents Industry RoB Low 12562742	N = 151 Mean Age 40 Female 58% Race NR Inpatient	Mania; YMRS ≥ 20 Schizoaffective Substance Abuse Other Mental Health Pregnant/Nursing Labs/Other Conditions	Risperidone 2-6 mg/day (Mean 4.0 mg/day) Adjunctive to Lithium or Divalproex or Carbamazepine	Placebo Adjunctive to Lithium or Divalproex or Carbamazepine	3 weeks	Response (YMRS 50% decrease) BPRS CGI HAM-D YMRS Withdrawal 44%

: Abbreviations: AIMS=Abnormal Involuntary Movement Scale; ASI=Addiction Severity Index; BAS=Behavioral Approach System; BID=Twice a day; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; C=Comparison; CGI-BP=Clinical Global Impressions Scale, Bipolar; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-I= Clinical Global Impressions-Improvement; CGI-S== Clinical Global Impressions-Severity Scale; DSM-IV-TR= Diagnostic and statistical manual, 4^th edition, Text Revision; EPS=extrapyramidal symptoms; FAST=Functional Assessment Short Test; GAF=General Assessment of Functioning Scale; GAS= Global Assessment Scale; HAM-D=Hamilton Scale for Depression; HAMD-21=Hamilton Rating Scale for Depression (21-items); HDRS-21=Hamilton Depression Rating Scale (21=items); ISST=International Suicide Prevention Trial Scale for Suicidal Thinking; LIFE-RIFT=Longitudinal Interval Follow-up Evaluation-Rating Impaired Functioning Tool; MADRS=Montgomery-Asberg Depression Rating Scale; NOS=not otherwise specified; NR=not reported; OR=Odds Ratio; PANSS=Positive and Negative Syndrome Scale; PAS=Premornid Adjustment Scale; PGI-I=Patient Global Impression Improvement; PMID=PubMed Identification Number; QLS=Quality of Life Scale; RCT=randomized controlled trial; RDQ=Readiness to Discharge Questionnaire; ROB=risk of bias; SANS=Scale for the Assessment of Negative Symptoms; SAPS=Scale for the Assessment of Positive Symptoms; SAS=Simpson Angus Scale; SF-36=36-Item Short Form Health Survey; UKU=UKU rating scale; YMRS = Young Mania Rating Scale

Appendix Table E64Summary risk of bias assessments: risperidone plus mood stabilizers for acute mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Risperidone	Yatham, 2003⁵⁵ Industry 12562742	Low	A well described and reported study with some minor lack of disclosure in blinding procedure and adverse events reporting. 44% dropout.

: Abbreviations: ITT=intention to treat; PMID=PubMed Identification Number

Appendix Table E65Outcomes summary: risperidone plus mood stabilizers versus placebo for acute mania

Drug	Study PMID RoB	Responder/Remitter	Symptom	Function	Other	AE
Risperidone adjunctive vs. placebo	Yatham, 2003⁵⁵ 12562742 Low	Response, Mean Difference 3 weeks 17.7% (95% CI 0.8-33.5); p<0.05 Favors intervention	YMRS, Mean Difference in Change Score 3 weeks -4.2 (95% CI −7.60, 0.53); p=0.09 NS HAM-D 3 weeks NS No statistical test reported BPRS, Mean Change 3 weeks Risperidone=-10.1 Placebo=-4.8 p=0.01 Favors intervention	CGI-BP, Mean Difference in Responders 3 weeks 17.5% (95% CI 1.1-33.9) Favors Intervention	Overall Withdrawal 3 weeks Risperidone=36% Placebo=52% Mean difference in completion rates=16% (95% CI 0.32, 31.68) Favors Intervention	One or More AEs, Between Group Difference 3 weeks 6% (95% CI −9.9, 21.9) NS EPS Symptoms 3 weeks Risperidone=16/75 Placebo=8/75 P=0.013

: Abbreviations: AE=Adverse Events; ASI=Addiction Severity Index; BPRS=Brief Psychiatric Rating Scale; CGI-Bp=Clinical Global Impresions Scale for Bipolar Disorder; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S=Clinical Global Impressions, Severity Scale; CI=Confidence Interval; EPS=extrapyramidal symptoms; GAF=General Assessment of Functioning Scale; HAM-D=Hamilton Scale for Depression; MADRS=Montgomery-Asberg Syndrome Scale; NR=not reported; NS=not significant; OR=Odds Ratio; PAS=Premorbid Adjustment Scale; PMID=PubMed Identification Number; QLS=Quality of Life Scale; ROB=risk of bias; SAE=Serious Adverse Events; SE=Standard Error; UKU=UKU rating scale; YMRS = Young Mania Rating Scale

Appendix Table E66Strength of evidence assessment: risperidone plus mood stabilizers versus placebo for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Risperidone adjunctive vs. placebo	Response 3 wks YMRS 3 wks CGI-BP 3 wks Withdrawal – overall	1 RCT (n=150)	See table above	Low	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; NS=not significant; RCT=randomized controlled trial; YMRS = Young Mania Rating Scale
: Notes:
1: Publication bias for antipsychotics, antidepressants, and behavioral interventions for depressive disorders is suspected.
2: Data were generally imprecise due to missing data from high attrition rates, which was commonly dealt with by Last Observation Carried Forward (LOCF). LOCF requires an assumption that the health status of patients who dropped out of the trial would not have changed had future observations been recorded, a strong assumption in the context of bipolar disorder research.

Section 14. Ziprazidone Plus Mood Stabilizer

Appendix Table E67Characteristics of eligible studies: ziprasidone plus mood stabilizer drug treatments for acute mania

Study, Year Design Location Funder Risk of Bias PMID	# Randomized Age (mean) Sex (% Female) Race (% White) Diagnosis (% BP I, II, NOS) Setting	Inclusions Key Exclusions	Intervention Dosage	Comparison Dosage	Follow-up Duration	Outcomes Reported Withdrawal (%) at endpoint
Sachs, 2012⁵⁶ RCT Multisite US Industry RoB High 23218157	N = 680 Mean Age 41 Female 50% White 65% BP I 100% Outpatient	Mania; YMRS ≥ 18 with 25% improvement between screening and baseline; current episode ≤ 3 months First manic episode Schizoaffective Substance Abuse Other Mental Health Conditions Taking Other Meds Labs/Other Conditions	Low Dose Ziprasidone (40-80 mg/day) Adjunctive to Lithium/Valproate OR High Dose Ziprasidone (120-160 mg/day) Adjunctive to Lithium/Valproate	Placebo Adjunctive to Lithium/Valproate	3 weeks	CGI-I CGI-S GAF LIFE-RIFT MADRS PANSS YMRS Withdrawal 42%

: Abbreviations: AIMS=Abnormal Involuntary Movement Scale; ASI=Addiction Severity Index; BAS=Behavioral Approach System; BID=Twice a day; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; C=Comparison; CGI-BP=Clinical Global Impressions Scale, Bipolar; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-I= Clinical Global Impressions-Improvement; CGI-S== Clinical Global Impressions-Severity Scale; DSM-IV-TR= Diagnostic and statistical manual, 4^th edition, Text Revision; EPS=extrapyramidal symptoms; FAST=Functional Assessment Short Test; GAF=General Assessment of Functioning Scale; GAS= Global Assessment Scale; HAM-D=Hamilton Scale for Depression; HAMD-21=Hamilton Rating Scale for Depression (21-items); HDRS-21=Hamilton Depression Rating Scale (21=items); ISST=International Suicide Prevention Trial Scale for Suicidal Thinking; LIFE-RIFT=Longitudinal Interval Follow-up Evaluation-Rating Impaired Functioning Tool; MADRS=Montgomery-Asberg Depression Rating Scale; NOS=not otherwise specified; NR=not reported; OR=Odds Ratio; PANSS=Positive and Negative Syndrome Scale; PAS=Premornid Adjustment Scale; PGI-I=Patient Global Impression Improvement; PMID=PubMed Identification Number; QLS=Quality of Life Scale; RCT=randomized controlled trial; RDQ=Readiness to Discharge Questionnaire; ROB=risk of bias; SANS=Scale for the Assessment of Negative Symptoms; SAPS=Scale for the Assessment of Positive Symptoms; SAS=Simpson Angus Scale; SF-36=36-Item Short Form Health Survey; UKU=UKU rating scale; YMRS = Young Mania Rating Scale

Appendix Table E68Summary risk of bias assessments: ziprasidone plus mood stabilizers for acute mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Ziprasidone	Sachs, 2012⁵⁶ Industry 23218157	High	Randomization and blinding not disclosed. Did not address how 680 were randomized but only 656 treated and analyzed. ITT noted, but they call this a modified ITT.

: Abbreviations: ITT=intention to treat; PMID=PubMed Identification Number

Appendix Table E69Outcomes summary: ziprasidone plus mood stabilizers versus placebo for acute mania

Drug	Study PMID RoB	Responder/Remitter	Symptom	Function	Other	AE
Ziprasidone adjunctive vs. placebo	Sachs, 2012⁵⁶ 23218157 High	NR	YMRS Change 3 week Low dose NS High dose NS	CGI-S 3 week Low dose NS High dose NS GAF 3 week Low dose NS High dose NS	Overall Withdrawal Low dose 48/226 High dose 62/232 Placebo 38/222 Withdrawal Lack of efficacy Low dose 6/226 High dose 4/232 Placebo 8/222 Withdrawal Adverse event Low dose 15/226 High dose 33/232 Placebo 11/222	SAE 11 ziprasidone groups 6 placebo EPS Low dose 1.9% High dose 4.9% Placebo 0.5%

: Abbreviations: AE=Adverse Events; ASI=Addiction Severity Index; BPRS=Brief Psychiatric Rating Scale; CGI-Bp=Clinical Global Impresions Scale for Bipolar Disorder; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S=Clinical Global Impressions, Severity Scale; CI=Confidence Interval; EPS=extrapyramidal symptoms; GAF=General Assessment of Functioning Scale; HAM-D=Hamilton Scale for Depression; MADRS=Montgomery-Asberg Syndrome Scale; NR=not reported; NS=not significant; OR=Odds Ratio; PAS=Premorbid Adjustment Scale; PMID=PubMed Identification Number; QLS=Quality of Life Scale; ROB=risk of bias; SAE=Serious Adverse Events; SE=Standard Error; UKU=UKU rating scale;YMRS = Young Mania Rating Scale

Appendix Table E70Strength of evidence assessment: ziprasidone plus mood stabilizers versus placebo for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Ziprasidone adjunctive vs. placebo	YMRS 3 wks CGI-BP 3 wks Withdrawal	1 RCT (n=680)	See table above	High	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; NS=not significant; RCT=randomized controlled trial; YMRS = Young Mania Rating Scale
: Notes:
1: Publication bias for antipsychotics, antidepressants, and behavioral interventions for depressive disorders is suspected.
2: Data were generally imprecise due to missing data from high attrition rates, which was commonly dealt with by Last Observation Carried Forward (LOCF). LOCF requires an assumption that the health status of patients who dropped out of the trial would not have changed had future observations been recorded, a strong assumption in the context of bipolar disorder research.

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Butler M, Urosevic S, Desai P, et al. Treatment for Bipolar Disorder in Adults: A Systematic Review [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2018 Aug. (Comparative Effectiveness Review, No. 208.) Appendix E, Antipsychotics for Mania.
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