Other Drugs for Acute 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 GOther Drugs for Acute Mania

Section 1. Allopurinol

Appendix Table G1Characteristics of eligible studies: allopurinol 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
Jahangard, 2014¹ RCT Singlesite Iran Nonprofit RoB Low 24953766	N = 60 Mean Age NR Female NR Race NR BP I 100% Inpatient	Manic; YMRS ≥ 28 Schizoaffective Substance Abuse Other Mental Health Pregnant/Nursing	Allopurinol 600 mg/day + sodium valproate (15–20 mg/kg) and benzodiazepines	Placebo + sodium valproate (15–20 mg/kg) and benzodiazepines	4 weeks	YMRS Remission (YMRS≤7) CGI Withdrawal 18%
Weiser, 2014² RCT Multisite Romania Nonprofit RoB High 24712840	N = 180 Mean Age 47 Female 66% White 100% BP I 100% Inpatient or Outpatient	Manic; Clinical Interview in DSM-IV treated with mood stabilizer or neuroleptics for between 3 days and 2 weeks. None Specified	Allopurinol 300 mg/day + mood stabilizer and/or antipsychotic	Placebo+ mood stabilizer and/or antipsychotic	6 weeks	Response (YMRS≥50% improvement) YMRS CGI-BP PANSS AEs Withdrawal 17%
Fan, 2012³ RCT Singlesite United States Nonprofit RoB Medium 22420596	N = 27 Mean Age 43 Female 50% White 63% BP I 100% Outpatient	Manic; YMRS≥14 partial response to lithium, valproate, carbamazepine, or atypical antipsychotics Substance Abuse Other Mental Health Pregnant/Nursing Labs/Other Conditions	Allopurinol 600 mg/day (300 mg/day first week) Current psychiatric medications	Placebo + current psychiatric medications	6 weeks	YMRS HAM-D CGI SDS Q-LES-Q Withdrawal 15%
Machado-Vieira, 2008⁴ RCT Brazil Non-Profit RoB Moderate 18681754	N = 180 Mean Age 29.3 Female 59% White NR BP I 100% Not Disclosed	Manic; YMRS≥22 Schizoaffective Substance abuse Other mental health Taking other meds Labs/other conditions	T1: Allopurinol 60 mg/day T2: Dipyridamole 200 mg/day Lithium 600–900 mg/day serum level 0.6–1.2 mmol/L (mean 0.99 mmol/L)	Placebo Lithium 600–900 mg/day serum level 0.6–1.2 mmol/L (mean 0.95 mmol/L)	4 weeks	CGI-S Remission (YMRS≤7) (YMRS≤12) Response (50% improved YMRS) Adverse Events Lab Values Withdrawal 20%

: Abbreviations: AE=Adverse Effects; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; CGI=Clinical Global Impressions; CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S=Clinical Global Impressions, Severity Scale; DSM-IV= Diagnostic and statistical manual, 4^th edition; EPS=Extrapyramidal Symptoms; GAF=General Assessment of Functioning Scale; GAS= Global Assessment Scale; HAM-D=Hamilton Depression Rating Scale; MADRS=Montgomery-Asberg Depression Rating Scale; NOS=not otherwise specified; NR= not reported; Q-LES-Q=Quality of Life Enjoyment and Satisfaction Questionnaire; PANSS=Positive and Negative Syndrome Scale; PMID=PubMed Identification Number; RCT= Randomized Controlled Trial; RoB=risk of bias; SAE=Serious Adverse Events; SDS=Sheehan Disability Scale; T=Trial; YMRS = Young Mania Rating Scale

Appendix Table G2Summary risk of bias assessments: allopurinol for mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Allopurinol	Jahangard, 2014¹ No external funding 24953766	Low	No sources of bias identified.
	Weiser, 2014² Non-Profit 24712840	High	Randomization and blinding not described. The original study design allows for any prescribed adjunctive medication so the medication effects cannot be localized to one drug. These treatments are not measured as part of the baseline or endpoint characteristics to ensure comparison group is similar to treatment group.
	Fan, 2012³ Not reported 22420596	Moderate	Randomization and blinding procedures not described.
	Machado-Vieira, 2008⁴ Non-Profit 18681754	Moderate	22% (39/180) of patients randomized not included in results (censored due to discontinuance), unclear how this group compares to general population. Dropout rates appear similar.

: Abbreviations: PMID=PubMed Identification Number; RCT=randomized controlled trial;

Allopurinol 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 G1Allopurinol vs. placebo – YMRS

Appendix Figure G2Allopurinol vs. placebo – CGI

Appendix Figure G3Allopurinol vs. placebo – overall withdrawal

Appendix Table G3Outcomes summary: allopurinol for mania vs. inactive control

Comparison	Study ROB PMID	Responder/Remitter	Symptom	Function	Other	AE
Allopurinol + mood stabilizers vs. placebo + mood stabilizers	Jahangard, 2014¹ Low 24953766	Remission (YMRS≤7) 4 weeks Allopurinol: 24/30 Placebo: 1/27 OR: 9.46 (1.19,81.57)	See forest plot G1 above	See forest plot G2 above	See forest plot G3 above Withdrawal Overall: 17% Efficacy: NR AEs: NR	No reported SAE
	Weiser, 2014² High 24712840	Response (YMRS≥50% decrease) 4 weeks Allopurinol: 34/90 Placebo: 35/90 NS OR 0.95 (0.52,1.74)	See forest plot G1 above	See forest plot G2 above	See forest plot G3 above Withdrawal Overall: 17% Efficacy: NR AEs: NR	No reported SAE
	Fan, 2012³ Moderate 22420596	NR	See forest plot G1 above	See forest plot G2 above	See forest plot G3 above Withdrawal Overall: 15% Efficacy: NR AEs: NR	NR
	Machado-Vieira, 2008⁴ Moderate 18681754	Remission (YMRS≤7) 4 weeks Allopurinol: 32/45 Placebo: 15/46 OR: 5.09 (2.09,12.41) Response (YMRS≥50% decrease) 4 weeks Allopurinol: 36/45 Placebo: 29/56 NS 2.34 (0.91, 6.03)	See forest plot G1 above	See forest plot G2 above Linear mixed model showed drug main effect was significant (p=0.004), and mixed effects with time were significant (p≤0.001)	NR Withdrawal Overall: 22% Efficacy: 5.6% AEs: 5.56	No reported SAE

: Abbreviations: AE=Adverse Events; BMI=Body Mass Index; CI=Confidence Interval; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S= Clinical Global Impressions, Severity Scale; EPS=extrapyramidal symptoms; GAF=General Assessment of Functioning Scale; GAS=Global Assessment Scale; NR=not reported; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; RCT=randomized controlled trial; SAE=Serious Adverse Events; SD=standard deviation; YMRS = Young Mania Rating Scale

Appendix Table G4Strength of evidence assessment: allopurinol for mania vs. inactive control

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Allopurinol + lithium vs. placebo + lithium	Remission 4 wks	2 RCT (n=96)	See table above	Moderate	Inconsistent	Direct	Imprecise	Insufficient
	Response 4 wks	2 RCT (n=96)	See table above	High	Consistent	Direct	Imprecise	Insufficient
	YMRS 4 wks CGI 4 wks Overall Withdrawal	4 RCT (n=355)	NS	Moderate	Consistent	Direct	Imprecise	Insufficient

: Abbreviations: CGI= Clinical Global Impressions; CGI-S=Clinical Global Impressions, Severity Scale; IPD=Individual Patient Data; 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 G5Outcomes summary: allopurinol for mania vs. active control

Drug	Study Comparison PMID	Responder/Remitter	Symptom	Function	Other	AE
Allopurinol + lithium vs. Dipyridamole + lithium	Machado-Vieira, 2008⁴ Moderate 18681754	Remission (YMRS≤7) Favors Allopurinol p=0.03 Response (YMRS≥50% decrease) NS	YMRS 4 weeks Mean change Favors Allopurinol p<0.01	CGI-S 4 weeks Linear mixed model Favors Allopurinol d=0.29 (0.09, 0.49)	NR Overall Withdrawal Allopurinol=15/60 Dipyridamole=10/60 NS Withdrawal lack of effect Allopurinol=3/60 Dipyridamole=5/60 NS Withdrawal adverse events Allopurinol=0/60 Dipyridamole=1/60 NS	SAE 1 dipyridmol patient severe skin rash

: Abbreviations: AE=Adverse Events; BMI=Body Mass Index; CGI=Clinical Global Impressions; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CI=Confidence Interval; EPS=extrapyramidal symptoms; GAF=General Assessment of Functioning Scale; NR=not reported; NS=not significant; PMID=PubMed Identification Number; RR=Risk Ratio; SAE=Serious Adverse Events; SD=standard deviation; YMRS = Young Mania Rating Scale

Appendix Table G6Strength of evidence assessment: allopurinol for mania vs. active control

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Allopurinol + lithium vs. Dipyridamole + lithium	Remission 4 wks Response 4 wks YMRS 4 wks CGI 4 wks Withdrawals	1 RCT (n=120)	See table above	Moderate	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: CGI= Clinical Global Impressions; CI=Confidence Interval; GAF=General Assessment of Functioning Scale; IPD=Individual Patient Data; 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. Dipyridamole

Appendix Table G7Characteristics of eligible studies: dipyridamole 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
Machado-Vieira, 2008⁴ RCT Brazil Non-Profit RoB Moderate 18681754	N = 180 Mean Age 29.3 Female 59% White NR BP I 100% Not Disclosed	Manic; YMRS≥22 Schizoaffective Substance abuse Other mental health Taking other meds Labs/other conditions	T1: Allopurinol 60 mg/day T2: Dipyridamole 200 mg/day Lithium 600–900 mg/day serum level 0.6–1.2 mmol/L (mean 0.99 mmol/L)	Placebo Lithium 600–900 mg/day serum level 0.6–1.2 mmol/L (mean 0.95 mmol/L)	4 weeks	CGI-S Remission (YMRS≤7) (YMRS≤12) Response (50% improved YMRS) Adverse Events Lab Values Withdrawal 20%

: Abbreviations: AE=Adverse Effects; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; CGI=Clinical Global Impressions; CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S=Clinical Global Impressions, Severity Scale; DSM-IV= Diagnostic and statistical manual, 4^th edition; EPS=Extrapyramidal Symptoms; GAF=General Assessment of Functioning Scale; GAS= Global Assessment Scale; HAM-D=Hamilton Depression Rating Scale; MADRS=Montgomery-Asberg Depression Rating Scale; NOS=not otherwise specified; NR= not reported; Q-LES-Q=Quality of Life Enjoyment and Satisfaction Questionnaire; PANSS=Positive and Negative Syndrome Scale; PMID=PubMed Identification Number; RCT= Randomized Controlled Trial; RoB=risk of bias; SAE=Serious Adverse Events; SDS=Sheehan Disability Scale; T=Trial; YMRS = Young Mania Rating Scale

Appendix Table G8Summary risk of bias assessments: dipyridamole for mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Dipyridamole	Machado-Vieira, 2008⁴ Non-Profit 18681754	Moderate	22% (39/180) of patients randomized not included in results (censored due to discontinuance), unclear how this group compares to general population. Dropout rates appear similar.

: Abbreviations: PMID=PubMed Identification Number; RCT=randomized controlled trial

Appendix Table G9Outcomes summary: dipyridamole for mania vs. inactive control

Comparison	Study ROB PMID	Responder/Remitter	Symptom	Function	Other	AE
Dipyridamole + lithium vs. placebo + lithium	Machado-Vieira, 2008⁴ Moderate 18681754	Remission (YMRS≤7) NR Response (YMRS≥50% decrease) NR	YMRS 4 weeks NS NR Linear mixed model showed drug main effect was not significant (p=0.11)	CGI-S 4 weeks NS p=0.13 Linear mixed model showed drug main effect was significant (p=0.004), and mixed effects with time were significant (p≤0.001)	NR Overall Withdrawal Dipyridamole=10/60 Placebo=14/60 NS Withdrawal lack of efficacy Dipyridamole=5/60 Placebo=7/60 NS Withdrawal adverse events Dipyridamole=1/60 Placebo=0/60 NS	1 dipyridamole participant with severe edverse event skin rash

: Abbreviations: AE=Adverse Events; BMI=Body Mass Index; CI=Confidence Interval; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S= Clinical Global Impressions, Severity Scale; EPS=extrapyramidal symptoms; GAF=General Assessment of Functioning Scale; GAS=Global Assessment Scale; NR=not reported; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; RCT=randomized controlled trial; SAE=Serious Adverse Events; SD=standard deviation; YMRS = Young Mania Rating Scale

Appendix Table G10Strength of evidence assessment: dipyridamole for mania vs. inactive control

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Dipyridamole + lithium vs. placebo + lithium	YMRS 4 wks CGI-S 4 wks Withdrawals	1 RCT (n=120)	See table above	Moderate	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: CGI= Clinical Global Impressions; CGI-S=Clinical Global Impressions, Severity Scale; IPD=Individual Patient Data; 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. Celecoxib

Appendix Table G11Characteristics of eligible studies: celecoxib 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
Arabzadeh, 2015⁵ RCT Iran University RoB Low 26291962	N = 48 Mean Age 31.4 Female 35% White NR BP I 100% Inpatient	Manic; YMRS≥20 Schizoaffective Substance abuse Other mental health Taking other meds Labs/other conditions	Celecoxib 400 mg/day	Placebo	6 weeks	YMRS HAM-D Remission (YMRS≤7) Time to Remission Response (YMRS≥50% decrease) Adverse Events Withdrawal 4%

: Abbreviations: AE=Adverse Effects; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; CGI=Clinical Global Impressions; CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S=Clinical Global Impressions, Severity Scale; DSM-IV= Diagnostic and statistical manual, 4^th edition; EPS=Extrapyramidal Symptoms; GAF=General Assessment of Functioning Scale; GAS= Global Assessment Scale; HAM-D=Hamilton Depression Rating Scale; MADRS=Montgomery-Asberg Depression Rating Scale; NOS=not otherwise specified; NR= not reported; Q-LES-Q=Quality of Life Enjoyment and Satisfaction Questionnaire; PANSS=Positive and Negative Syndrome Scale; PMID=PubMed Identification Number; RCT= Randomized Controlled Trial; RoB=risk of bias; SAE=Serious Adverse Events; SDS=Sheehan Disability Scale; T=Trial; YMRS = Young Mania Rating Scale

Appendix Table G12Summary risk of bias assessments: celecoxib for mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Celecoxib	Arabzadeh, 2015⁵ University 26291962	Low	No sources of bias identified

: Abbreviations: PMID=PubMed Identification Number; RCT=randomized controlled trial;

Appendix Table G13Outcomes summary: celecoxib for mania vs. inactive control

Comparison	Study ROB PMID	Responder/Remitter	Symptom	Function	Other	AE
Celecoxib vs. placebo	Arabzadeh, 2015⁵ Low 26291962	Response (YMRS≥50% decrease) 3 weeks NS (p=0.08) 6 weeks NS p=0.11 Remission (YMRS≤7) 3 weeks NS p=0.15 6 weeks Favors celecoxib p=0.002	YMRS 3 weeks Favors celecoxib Mean difference −5.17 (−9.61, −0.74) p=0.006 6 weeks Favors celecoxib p<0.001	NR	NR Withdrawal Celecoxib=1/24 Placebo=1/24 NS	Serious Adverse Events 6 weeks 0 in both arms Deaths 6 weeks 0 in both arms EPS NR

: Abbreviations: AE=Adverse Events; BMI=Body Mass Index; CI=Confidence Interval; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S= Clinical Global Impressions, Severity Scale; EPS=extrapyramidal symptoms; GAF=General Assessment of Functioning Scale; GAS=Global Assessment Scale; NR=not reported; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; RCT=randomized controlled trial; SAE=Serious Adverse Events; SD=standard deviation; YMRS = Young Mania Rating Scale

Appendix Table G14Strength of evidence assessment: celecoxib for mania vs. inactive control

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Celecoxib vs. placebo	Remission 3 wks Response 3 wks YMRS 3 wks Withdrawals	1 RCT (n=44)	See table above	Low	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: CGI= Clinical Global Impressions; CGI-S=Clinical Global Impressions, Severity Scale; IPD=Individual Patient Data; 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. Donepezil

Appendix Table G15Characteristics of eligible studies: donepezil 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
Chen, 2013⁶ RCT China Non-profit RoB Moderate 23807849	N = 30 Mean Age 34.1 Female 40% White (%) NR BP I 100% Inpatient	Manic; YMRS>20 Schizoaffective Substance abuse Other mental health Taking other meds Pregnant/nursing Labs/other conditions	Donepezil 10 mg/day Lithium 600–900 mg/day serum level 0.8–1.2 mmol/L (mean 0.83 mmol/L)	Placebo Lithium 600–900 mg/day serum level 0.8–1.2 mmol/L (mean 0.82 mmol/L)	4 weeks	BPRS YMRS Response (YMRS decrease ≥50%) Remission (YMRS≤12) Adverse Events Withdrawal 0%

: Abbreviations: AE=Adverse Effects; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; CGI=Clinical Global Impressions; CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S=Clinical Global Impressions, Severity Scale; DSM-IV= Diagnostic and statistical manual, 4^th edition; EPS=Extrapyramidal Symptoms; GAF=General Assessment of Functioning Scale; GAS= Global Assessment Scale; HAM-D=Hamilton Depression Rating Scale; MADRS=Montgomery-Asberg Depression Rating Scale; NOS=not otherwise specified; NR= not reported; Q-LES-Q=Quality of Life Enjoyment and Satisfaction Questionnaire; PANSS=Positive and Negative Syndrome Scale; PMID=PubMed Identification Number; RCT= Randomized Controlled Trial; RoB=risk of bias; SAE=Serious Adverse Events; SDS=Sheehan Disability Scale; T=Trial; YMRS = Young Mania Rating Scale

Appendix Table G16Summary risk of bias assessments: donepezil for mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Donepezil	Chen, 2013⁶ Nonprofit 23807849	Moderate	Randomization and blinding procedures not described.

: Abbreviations: PMID=PubMed Identification Number; RCT=randomized controlled trial

Appendix Table G17Outcomes summary: donepezil for mania vs. inactive control

Comparison	Study ROB PMID	Responder/Remitter	Symptom	Function	Other	AE
Donepezil + lithium vs. placebo + lithium	Chen, 2013⁶ Moderate 23807849	Remission (YMRS≤12) 4 weeks NS p=0.27 Response (YMRS≥50% decrease) 4 weeks NS p=1.0	YMRS Decrease 4 weeks NS p=0.16	NR	No withdrawals	Reported no serious adverse events

: Abbreviations: AE=Adverse Events; BMI=Body Mass Index; CI=Confidence Interval; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S= Clinical Global Impressions, Severity Scale; EPS=extrapyramidal symptoms; GAF=General Assessment of Functioning Scale; GAS=Global Assessment Scale; NR=not reported; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; RCT=randomized controlled trial; SAE=Serious Adverse Events; SD=standard deviation; YMRS = Young Mania Rating Scale

Appendix Table G18Strength of evidence assessment: donepezil for mania vs. inactive control

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Donepezil + lithium vs. placebo + lithium	Response 4 wks Remission 4 wks YMRS 4 wks	1 RCT (n=30)	See table above	Moderate	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: CGI= Clinical Global Impressions; CGI-S=Clinical Global Impressions, Severity Scale; IPD=Individual Patient Data; 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. Endoxifen

Appendix Table G19Characteristics of eligible studies: endoxifen 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
Ahmad, 2016⁸ RCT India Industry ROB Low 27346789	N=66 Mean Age 33 Female 52% Race NR BP I 100% Inpatient	Manic/Mixed; YMRS ≥ 20 and CGI-S ≥ 4 New diagnosis Labs/other conditions Pregnant/nursing	Endoxifen oral enteric coated tablets at two fixed doses T1: 4 mg/day T2: 8 mg/day)	Divalproex 1000 mg/day	3 weeks	Response (YMRS decrease ≥50%) CGI-S YMRS MADRS Withdrawal 7%

: Abbreviations: AE=Adverse Effects; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; CGI=Clinical Global Impressions; CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S=Clinical Global Impressions, Severity Scale; DSM-IV= Diagnostic and statistical manual, 4^th edition; EPS=Extrapyramidal Symptoms; GAF=General Assessment of Functioning Scale; GAS= Global Assessment Scale; HAM-D=Hamilton Depression Rating Scale; MADRS=Montgomery-Asberg Depression Rating Scale; NOS=not otherwise specified; NR= not reported; Q-LES-Q=Quality of Life Enjoyment and Satisfaction Questionnaire; PANSS=Positive and Negative Syndrome Scale; PMID=PubMed Identification Number; RCT= Randomized Controlled Trial; RoB=risk of bias; SAE=Serious Adverse Events; SDS=Sheehan Disability Scale; T=Trial; YMRS = Young Mania Rating Scale

Appendix Table G20Summary risk of bias assessments: endoxifen for mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Endoxifen	Ahmad, 2016⁸ Industry 27346789	Low	Well-disclosed and reported study.

: Abbreviations: PMID=PubMed Identification Number; RCT=randomized controlled trial;

Appendix Table G21Outcomes summary table: endoxifen for mania vs. active control

Drug	Study Comparison PMID	Responder/Remitter	Symptom	Function	Other	AE
Endoxifen vs. divalproex	Ahmad, 2016⁸ Low 27346789	Response (YMRS≥50% decrease) 3 weeks NS Endoxifen 4 mg: 44% Endoxifen 8 mg: 64% Divalproex:: 72%	YMRS 3 weeks NS Mean change Endoxifen 4 mg:−12.65 Endoxifen 8 mg: −16.21 Divalproex:: −16.38	CGI-S 3 week Reported NS (details not reported)	2 patients withdrew due to adverse events 4 mg arm	Serious Adverse Events 3 weeks 2 4 mg arm (delusions) No deaths

: Abbreviations: AE=Adverse Events; BMI=Body Mass Index; CGI=Clinical Global Impressions; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CI=Confidence Interval; EPS=extrapyramidal symptoms; GAF=General Assessment of Functioning Scale; NR=not reported; NS=not significant; PMID=PubMed Identification Number; RR=Risk Ratio; SAE=Serious Adverse Events; SD=standard deviation; YMRS = Young Mania Rating Scale

Appendix Table G22Strength of evidence assessment: endoxifen for mania vs. active control

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Endoxifen vs. divalproex	Remission 3 wks YMRS 3 weeks CGI-S 3 weeks	1 RCT (4 mg: n=42 (8 mg: n=42)	See table above	Low	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: CGI= Clinical Global Impressions; CI=Confidence Interval; GAF=General Assessment of Functioning Scale; IPD=Individual Patient Data; 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. Gabapentin

Appendix Table G23Characteristics of eligible studies: gabapentin 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
Astaneh, 2012⁷ RCT Single-site Iran University RoB High 22978083	N = 60 Mean Age NR Female about 50% White NR BP I NR Inpatient	Mania; Not Defined Substance abuse	Gabapentin 900 mg/day Lithium NR	Placebo Lithium NR	6 week	YMRS Withdrawal 0

: Abbreviations: AE=Adverse Effects; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; CGI=Clinical Global Impressions; CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S=Clinical Global Impressions, Severity Scale; DSM-IV= Diagnostic and statistical manual, 4^th edition; EPS=Extrapyramidal Symptoms; GAF=General Assessment of Functioning Scale; GAS= Global Assessment Scale; HAM-D=Hamilton Depression Rating Scale; MADRS=Montgomery-Asberg Depression Rating Scale; NOS=not otherwise specified; NR= not reported; Q-LES-Q=Quality of Life Enjoyment and Satisfaction Questionnaire; PANSS=Positive and Negative Syndrome Scale; PMID=PubMed Identification Number; RCT= Randomized Controlled Trial; RoB=risk of bias; SAE=Serious Adverse Events; SDS=Sheehan Disability Scale; T=Trial; YMRS = Young Mania Rating Scale

Appendix Table G24Summary risk of bias assessments: gabapentin for mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Gabapentin	Astaneh, 2012⁷ University 22978083	High	Clinical and demographic traits at baseline not reported or compared for similarity. Blinding of staff and patients not addressed. Reporting is insufficient and may be misleading (e.g. missing values in graphs, missing error bars in graphs, raw data not provided/only sum of squares, asserts statistically meaningful improvement when improvement not shown statistically).

: Abbreviations: PMID=PubMed Identification Number; RCT=randomized controlled trial

Appendix Table G25Outcomes summary: gabapentin for mania vs. inactive control

Comparison	Study ROB PMID	Responder/Remitter	Symptom	Function	Other	AE
Gabapentin + lithium vs. placebo + lithium	Astaneh, 2012⁷ High 22978083	NR	YMRS Reported favors gabapentin. However, baseline YMRS gabapentin = ~50 while control = ~13.	NR	NR	NR

: Abbreviations: AE=Adverse Events; BMI=Body Mass Index; CI=Confidence Interval; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S= Clinical Global Impressions, Severity Scale; EPS=extrapyramidal symptoms; GAF=General Assessment of Functioning Scale; GAS=Global Assessment Scale; NR=not reported; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; RCT=randomized controlled trial; SAE=Serious Adverse Events; SD=standard deviation; YMRS = Young Mania Rating Scale

Appendix Table G26Strength of evidence assessment: gabapentin for mania vs. inactive control

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Gabapentin + lithium vs. placebo + lithium	YMRS 6 wks	1 RCT (n=60)	See table above	High	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: CGI= Clinical Global Impressions; CGI-S=Clinical Global Impressions, Severity Scale; IPD=Individual Patient Data; 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. Paliperidone

Appendix Table G27Characteristics of eligible studies: paliperidone 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
Berwaerts, 2012a⁹ RCT 3 Continents Industry ROB Moderate 20624657	N = 469 Mean Age 40 Female 47% White 50% BP I 100% Inpatient (at least 1 week) Outpatient (weeks 2–3)	Manic/Mixed; YMRS ≥ 20 with 1 manic or mixed episode in past three years Schizoaffective; Substance abuse; Other Mental Health Condition; Taking other medications; Pregnant/Nursing	Paliperdone extended release (separate 3,6,12 mg/day arms)	Placebo	3 weeks	CGI-BP-S GAF MADRS PANSS Scale for Suicide Ideation (SSI) YMRS SAE EPS Withdrawal 39%
Berwaerts, 2011¹⁰ RCT 3 Continents Industry ROB Moderate 20947174	n = 300 Mean Age 40 Female 46% White 77% BP I 100% Inpatient (at least 1 week) Outpatient (weeks 2–7)	Manic/Mixed; YMRS ≥ 20 First Manic Episode; Schizoaffective; Substance Abuse; Other Mental Health Conditions; Neurological Disorders; Taking other medications; Pregnant/Nursing	Paliperidone extended release 3–12 mg/day (mean 8.1 mg/day) Lithium 0.6–1.2 mEq/L (mean NR) Or Valproate 50–125 mcg/mL (mean NR)	Placebo NA Lithium 0.6–1.2 mEq/L (mean NR) Or Valproate 50–125 mcg/mL (mean NR)	7 weeks		CGI-BP-S GAF PANSS YMRS Response (YMRS decrease ≥50%) Remission (YMRS≤12) MADRS Adverse Events Withdrawal 37%
Vieta, 2010¹¹ RCT 3 weeks Multisite 4 Continents Industry RoB Moderate 20565430	N = 493 Mean Age 39 Female 42% White 68% BP I 100% Inpatient (at least 1 week) Outpatient (weeks 2–3)	Manic/Mixed; YMRS≥20; At least one episode within three years prior First Manic Episode Schizoaffective Substance abuse Other mental health Neurological disorders Labs/other conditions	Paliperidone extended release 3–12 mg/day (median/mode dosage 9 mg)	C1: Placebo C2: Quetiapine 400–800 mg/day	3 week (12 week excluded for attrition)	YMRS GAF PANSS CGI-BP-S Response (YMRS decrease ≥50%) Remission (YMRS≤12) Withdrawal 21% at 3 weeks
Berwaerts, 2012¹² RCT Multisite 5 Continents Industry RoB Moderate 22377512	N = 766 Mean Age 40 Female 52% White 62% BP I 100% Outpatient	Manic/Mixed; YMRS≥20; 2 previous mood episodes (1 of which manic/mixed) within past 3 years; First manic episode; Schizoaffective; Other mental health; Neurological disorders; Taking other meds; Pregnant/nursing; Labs/Other conditions	Paliperidone extended release 3–12 mg/day	Olanzapine 5–20 mg/day	15 weeks	Response (≥50% reduction in YMRS) Remission (YMRS and MADRS≤12) Withdrawal 49%

: Abbreviations: AE=Adverse Effects; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; CGI=Clinical Global Impressions; CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S=Clinical Global Impressions, Severity Scale; DSM-IV= Diagnostic and statistical manual, 4^th edition; EPS=Extrapyramidal Symptoms; GAF=General Assessment of Functioning Scale; GAS= Global Assessment Scale; HAM-D=Hamilton Depression Rating Scale; MADRS=Montgomery-Asberg Depression Rating Scale; NOS=not otherwise specified; NR= not reported; Q-LES-Q=Quality of Life Enjoyment and Satisfaction Questionnaire; PANSS=Positive and Negative Syndrome Scale; PMID=PubMed Identification Number; RCT= Randomized Controlled Trial; RoB=risk of bias; SAE=Serious Adverse Events; SDS=Sheehan Disability Scale; T=Trial; YMRS = Young Mania Rating Scale

Appendix Table G28Summary risk of bias assessments: paliperidone for mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Paliperidone extended release	Berwaerts, 2012¹² Industry 22377512	High	Very large dropout rate among all study arms, across all time periods
	Berwaerts, 2012a⁹ Industry 20624657	Moderate	Large dropout rate among all study arms; attrition 39%
	Vieta, 2010¹¹ Industry 20565430	Moderate (3 week only)	Moderate dropout rate among all study arms, across all time periods; raters may not be blinded
	Berwaerts, 2011¹⁰ Industry 20947174	Moderate	Large dropout rate among all study arms; attrition 37%

: Abbreviations: PMID=PubMed Identification Number; RCT=randomized controlled trial

Appendix Table G29Outcomes summary: paliperidone for mania vs. inactive control

Comparison	Study ROB PMID	Responder/Remitter	Symptom	Function	Other	AE
Paliperidone vs. placebo	Vieta, 2010¹¹ Moderate 20565430	Responders (YMRS decrease ≥50%) 3 weeks Favors Paliperidone Paliperidone=106/190 Placebo=36/104 p<0.001 Remission (YMRS≤12) 3 weeks Favors Paliperidone Paliperidone=99/190 Placebo=30/104 p<0.001	YMRS Change 3 weeks Favors treatment Least square mean difference between groups −5.5 (95% CI −7.57, −3.35) p<0.001	CGI-BP-S 3 week Paliperidone −2.0 (95%CI −4, 2) Placebo −0.5 (95%CI −4, 2) Favors Paliperidone p<0.001 GAF 3 weeks Favors treatment Mean difference treatment: 11.6 Placebo: 12.2 p<0.001	Overall Withdrawal Paliperidone=40/195 Placebo=41/105 Favors Paliperidone Withdrawal lack of effect Paliperidone=6/195 Placebo=19/105 Favors Paliperidone Withdrawal adverse events Paliperidone=9/195 Placebo=5/105 NS	Serious AE NR EPS No serious events in any treatment arm
Paliperidone vs. placebo	Berwaerts, 2012a⁹ Moderate 20624657	Responders (YMRS decrease ≥50%) 3 weeks NS Remission (YMRS≤12) 3 weeks NS	YRMS Change 3 weeks Least square mean difference Paliperidone 12 mg: −13.5 (9.17) n=109 Placebo: −10.1 (10.21) Difference between groups 3.4 n=115 p=0.025 Favors Paliperidone 12 mg (dose dependent)	CGI-BP-S 3 week NS GAF 3 weeks NS	Overall Withdrawal Paliperidone=132/347 Placebo=50/122 NS Withdrawal lackof effect Paliperidone=31/347 Placebo=24/122 Favors Paliperidone Withdrawal adverse events Paliperidone=25/347 Placebo=6/122 NS	Serious AE 1 death Paliperidone 6 mg (deemed not related) EPS Statistically significantly more in 12 mg paliperidon for akathisia and dystonia Treatment emergent depression: NS >7% weight gain NS
Paliperidone + mood stabilizers vs. placebo + mood stabilizers	Berwaerts, 2011¹⁰ Moderate 20947174	Remission (YMRS≤12) 6 weeks NS Paliperidone 60% Placebo 57% p=0.12 Response (YMRS≥50% decrease) 6 weeks NS Paliperidone 62% Placebo 56% p=0.24	YMRS 6 weeks Least squares mean difference NS p=0.16	CGI-BP-S 6 weeks NS p=0.26 GAF 6 weeks NS p=0.71	Suicide Ideation 1 in each group Overall Withdrawal Paliperidon=60/150 Placebo=51/150 NS Withdrawal lack of effect Paliperidone=12/150 Placebo=18/150 NS Withdrawal adverse events Paliperidone=12/150 Placebo=2/150 Favors Placebo	SAE 7 in each group; psychiatric disorders most common Treament emergent depression: 1% in each group Akathesia 8% vs. 1% Favored placebo. Weight increase≥7%: Paliperidone 15% Placebo 5%

: Abbreviations: AE=Adverse Events; BMI=Body Mass Index; CI=Confidence Interval; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S= Clinical Global Impressions, Severity Scale; EPS=extrapyramidal symptoms; GAF=General Assessment of Functioning Scale; GAS=Global Assessment Scale; NR=not reported; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; RCT=randomized controlled trial; SAE=Serious Adverse Events; SD=standard deviation; YMRS = Young Mania Rating Scale

Appendix Table G30Strength of evidence assessment: paliperidone for mania vs. inactive control

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Paliperidone vs. placebo	Remission 3 wks Response 3 wks CGI Withdrawal – overall	2 RCT (n=763)	See table above	Moderate	Inconsistent	Direct	Imprecise	Insufficient
	Withdrawal – adverse events	2 RCT (n=763)	NS	Moderate	Consistent	Direct	Imprecise	Low
	YMRS 3 wks Withdrawal lack of efficacy	2 RCT (n=763)	Favors Paliperidone possible dose response: NS at 3 and 6 mg, benefit at 12 mg or median dosage of 9 mg	Moderate	Consistent	Direct	Imprecise	Low
Paliperidone + mood stabilizers vs. placebo + mood stabilizers	Remission 6 wks Response 6 wks YMRS 6 wks CGI-S 6 wks Withdrawals	1 RCT (n=299)	See table above	Moderate	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: CGI= Clinical Global Impressions; CGI-S=Clinical Global Impressions, Severity Scale; IPD=Individual Patient Data; 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 G31Outcomes summary: paliperidone for mania vs. active control

Drug	Study Comparison PMID	Responder/Remitter	Symptom	Function	Other	AE
Paliperidone extended release vs. olanzapine	Berwaerts, 2012¹² Moderate 22377512	Response (YMRS decrease ≥50%) 15 weeks NS >70% responded overall Remission (YMRS≤12) 15 weeks NS >60% achieved remission	YMRS Least square mean difference 15 weeks NS −0.3 (−2.12, 1.57)	NR	Overall Withdrawal 15 weeks Paliperidone: 09/617 Olanzapine: 63/149 NS Withdrawal lack of effect Paliperidone:30/617 Olanzapine:5/149 NS Withdrawal adverse events Paliperidone:63/617 Olanzapine:13/149 NS	SAE Paliperidone: 42/614 Olanzapine: 10/148 NS
Paliperidone extended release vs. quetiapine	Vieta, 2010¹¹ Moderate 20565430	Response (YMRS decrease ≥50%) 3 week Paliperidone 55.8% Quetiapine 49% NS RR 1.1 (95% CI 0.94, 1.38) Remission (YMRS≤12) 3 week Paliperidone 52.1% Quetiapine 47.4% NS RR 1.1 (95% CI 0.90, 1.35)	YMRS Change 3 week LSM difference (Quet-Pali) 1.5 (95% CI −0.28, 3.22) NS p=0.099	GAF Change¹ 3 week Paliperidone 12.2 (sd 11.17) Quetiapine 11.6 (sd 11.96) NS p=NR CGI-BP-S 3 week Paliperidone −2.0 (95%CI −4, 2) Quetiapine −1.0 (95%CI −4, 2) NS p=NR	Switching 3 week Paliperidone 4.3% Quetiapine 2.7% NS p=NR Overall Withdrawal Paliperidone=40/195 Quetiapine=41/193 NS Withdrawal lack of effect Paliperidone=6/195 Quetiapine=15/105 Favors Paliperidone Withdrawal adverse events Paliperidone=9/195 Quetiapine=4/193 NS	SAE NR EPS No serious events in any treatment arm

: Abbreviations: AE=Adverse Events; BMI=Body Mass Index; CGI=Clinical Global Impressions; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CI=Confidence Interval; EPS=extrapyramidal symptoms; GAF=General Assessment of Functioning Scale; NR=not reported; NS=not significant; PMID=PubMed Identification Number; RR=Risk Ratio; SAE=Serious Adverse Events; SD=standard deviation; YMRS = Young Mania Rating Scale

Appendix Table G32Strength of evidence assessment: paliperidone for mania vs. active control

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Paliperidone extended release vs. olanzapine	Remission 15 wks Response 15 wks YMRS 15 wks Withdrawals	1 RCT (n=766)	See table above	High	Unknown	Direct	Imprecise	Insufficient
Paliperidone extended release vs. quetiapine	Remission 3 wks Response 3 wks YMRS 3 wks CGI 3 wks GAF 3 wks Withdrawals	1 RCT (n=388)	See table above	High	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: CGI= Clinical Global Impressions; CI=Confidence Interval; GAF=General Assessment of Functioning Scale; IPD=Individual Patient Data; 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. Tamoxifen

Appendix Table G33Characteristics of eligible studies: tamoxifen 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
Yildiz, 2008¹³ RCT Single-site Turkey Non-Profit RoB Moderate 18316672	N = 66 Mean Age 33 Female 52% Race NR BP I 100% Outpatient	Mania; YMRS≥20 Schizoaffective Substance abuse Other mental health Neurological disorders Taking other meds Pregnant/nursing	Tamoxifen 20–80 mg/twice daily	Placebo	3 week	CGI-BP-S HAM-D MADRS PANSS YMRS Response (YMRS decrease ≥50%) Withdrawal 24%

: Abbreviations: AE=Adverse Effects; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; CGI=Clinical Global Impressions; CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S=Clinical Global Impressions, Severity Scale; DSM-IV= Diagnostic and statistical manual, 4^th edition; EPS=Extrapyramidal Symptoms; GAF=General Assessment of Functioning Scale; GAS= Global Assessment Scale; HAM-D=Hamilton Depression Rating Scale; MADRS=Montgomery-Asberg Depression Rating Scale; NOS=not otherwise specified; NR= not reported; Q-LES-Q=Quality of Life Enjoyment and Satisfaction Questionnaire; PANSS=Positive and Negative Syndrome Scale; PMID=PubMed Identification Number; RCT= Randomized Controlled Trial; RoB=risk of bias; SAE=Serious Adverse Events; SDS=Sheehan Disability Scale; T=Trial; YMRS = Young Mania Rating Scale

Appendix Table G34Summary risk of bias assessments: tamoxifen for mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Tamoxifen	Yildiz, 2008¹³ Non-Profit 18316672	Moderate	Blinding of patients, staff, raters not described; minor differences at baseline regarding pretreatment drugs may create residual confounding

: Abbreviations: PMID=PubMed Identification Number; RCT=randomized controlled trial;

Appendix Table G35Outcomes summary: tamoxifen for mania vs. inactive control

Comparison	Study ROB PMID	Responder/Remitter	Symptom	Function	Other	AE
Tamoxifen vs. placebo	Yildiz, 2008¹³ Moderate 18316672	Response (YMRS decrease ≥50%) 3 weeks Favors tamoxifen Tamoxifen=14/29 Placebo=1/21 p=0.003 Remission (YMRS≤12) 3 weeks Favors tamoxifen Tamoxifen=8/29 Placebo=0/21 p=0.03	YMRS Decrease Rate Over 3 weeks Favors tamoxifen Linear mixed model p<0.001 YMRS (Mean SD) Week 0 Tamoxifen 38.6 (5.0) Placebo 37.2 (6.6) Week 3 Tamoxifen 20.3 (11.2) Placebo 40.1 (10.4)	NR	NR Withdrawal Tamoxifen=6/35 Placebo=10/31 NS	Serious Adverse Events 1 Tamoxifen – Suicide Attempt 1 Placebo – Suicide Attempt

: Abbreviations: AE=Adverse Events; BMI=Body Mass Index; CI=Confidence Interval; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S= Clinical Global Impressions, Severity Scale; EPS=extrapyramidal symptoms; GAF=General Assessment of Functioning Scale; GAS=Global Assessment Scale; NR=not reported; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; RCT=randomized controlled trial; SAE=Serious Adverse Events; SD=standard deviation; YMRS = Young Mania Rating Scale

Appendix Table G36Strength of evidence assessment: tamoxifen for mania vs. inactive control

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Tamoxifen vs. placebo	Remission 3 wks Response 3 wks YMRS 3 wks Withdrawals	1 RCT (n=50)	See table above	Low	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: CGI= Clinical Global Impressions; CGI-S=Clinical Global Impressions, Severity Scale; IPD=Individual Patient Data; 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. Topiramate

Appendix Table G37Characteristics of eligible studies: topiramate 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
Bahk, 2005¹⁴ Open-label RCT Multisite South Korea Industry ROB High 15610953	N=74 Mean Age 37 Female 51% Race Asian BP-I 100% Outpatient	Mania YMRS≥20 Other mental health Pregnant/nursing Labs/other conditions Taking other meds	Topiramate average 220.6 mg/day + Risperidone average 3.4 mg/day	Divalproex average 908.3 mg/day Risperidone average 3.3 mg/day	3 week	YMRS CGI Adverse Events Withdrawal 18%
Chengappa, 2006¹⁵ RCT Multisite US Low Industry RoB Low 17196048	N = 287 Mean Age 40 Female 56% White 84% BP I 100% Outpatient	Manic/Mixed; YMRS≥18 Recevied lithium or valproate at least 6 weeks, including stable dose 2 weeks prior to screening within specified serum levels Substance abuse Other mental health Neurological disorders Taking other meds Pregnant/nursing Labs/other conditions	T1: Topiramate 50–400mg/day (mean 6.2 mcg/mL day 42, 7.8 mcg/ml day 84) Lithium mean 0.7 mEq/L Valproate mean 69.8 mcg/ml	Placebo Lithium mean 0.7 mEq/L Valproate mean 71.0 mcg/ml	12 week	YMRS CGI-S BPRS MADRS GAS Weight Response (≥50% improvement in YRMS) Withdrawal 38%
Kushner, 2006¹⁶ Pooled Analysis of 4 RCTs (3 week data) Multisite 6 Continents Industry RoB Low 16411977	N = 876 (includes only 400 mg/day topiramte arms and placebo arms Mean Age 41 Female 51% White 75% BP I 100% Inpatient (at least 4 days, as clinically warranted)	Manic/Mixed; YMRS≥20 First Manic Episode Schizoaffective Substance abuse Other mental health Taking other meds Pregnant/nursing Labs/other conditions	Topiramate 400mg/day (mean 313mg/day) (only 400 mg/day arms were common across pooled studies)	C1: Placebo C2: Lithium 300–1800 mg/day (0.8–1.2mEq/L)	3 week	Weight YMRS Withdrawal 27%

: Abbreviations: AE=Adverse Effects; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; CGI=Clinical Global Impressions; CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S=Clinical Global Impressions, Severity Scale; DSM-IV= Diagnostic and statistical manual, 4^th edition; EPS=Extrapyramidal Symptoms; GAF=General Assessment of Functioning Scale; GAS= Global Assessment Scale; HAM-D=Hamilton Depression Rating Scale; MADRS=Montgomery-Asberg Depression Rating Scale; NOS=not otherwise specified; NR= not reported; Q-LES-Q=Quality of Life Enjoyment and Satisfaction Questionnaire; PANSS=Positive and Negative Syndrome Scale; PMID=PubMed Identification Number; RCT= Randomized Controlled Trial; RoB=risk of bias; SAE=Serious Adverse Events; SDS=Sheehan Disability Scale; T=Trial; YMRS = Young Mania Rating Scale

Appendix Table G38Summary risk of bias assessments: topimarate for mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Topiramate	Bahk, 2005¹⁴ Industry 15610953	High	Randomization and allocation concealment not specified, open label dosing
	Kushner, 2006¹⁶ Industry 16411977	Low	Well-disclosed and reported study (RCTs unique to this publication.)
	Chengappa, 2006¹⁵ Industry 17196048	Low	Well-disclosed and reported study

: Abbreviations: PMID=PubMed Identification Number; RCT=randomized controlled trial

Appendix Table G39Outcomes summary: topiramate for mania vs. inactive control

Comparison	Study ROB PMID	Responder/Remitter	Symptom	Function	Other	AE
Topiramate vs. placebo	Kushner, 2006¹⁶ Low 16411977	NR	YMRS Change 3 weeks NS Mean difference (top-plac) 0.60 (95% CI −0.85, 2.0) p=0.418 n=434 I, n=317 C	NR	Overall Withdrawal Topiramte=123/331 Placebo=85/317 Favors Placebo Withdrawal lack of effect Topiramate=52/331 Placebo=39/317 NS Withdrawal adverse events Topiramate=20/331 Placebo=9/317 Favors Placebo	SAE Topiramate 3% Placebo 2% Suicide Attempt 3 weeks Topiramate 2/656 Placebo 0/429 (reported over 4 pooled RCTs, not 3 monotherapy tests)
Topiramate+mood stabilizer vs. placebo+mood stabilizer	Chengappa, 2006¹⁵ Low 17196048	Response (YMRS≥50% decrease) 12 weeks NS Topiramate 39% Placebo 38% p=0.914	YMRS Change 12 weeks NS Topiramate −10.1±8.7 Placebo −9.6±8.2 p=0.797	CGI-S Change 12 weeks NS Topiramate −0.9±1.1 Placebo −0.9±1.1 p=0.698 GAS Change 12 weeks NS Topiramate 7.2±9.9 Placebo 7.1±11.5 p=0.838	BMI Change 12 weeks Favors Topiramate Topiramate −0.84±1.2 kg/m² Placebo 0.07±1.1 kg/m² p<0.001 Suicide Ideation Topiramate 1 patient Placebo 2 patients Overall Withdrawal Topiramate=57/143 Placebo=53/144 NS Withdrawal lack of effect Topiramate=6/143 Placebo=4/144 NS Withdrawal adverse events Topiramate=20/143 Placebo=10/144 Favors Placebo	NR

: Abbreviations: AE=Adverse Events; BMI=Body Mass Index; CI=Confidence Interval; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-S= Clinical Global Impressions, Severity Scale; EPS=extrapyramidal symptoms; GAF=General Assessment of Functioning Scale; GAS=Global Assessment Scale; NR=not reported; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; RCT=randomized controlled trial; SAE=Serious Adverse Events; SD=standard deviation; YMRS = Young Mania Rating Scale

Appendix Table G40Strength of evidence assessment: topiramate for mania vs. inactive control

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Topiramate vs. placebo	YMRS 3 wks Withdrawal – lack of effect	4 RCT (1 IPD) (n=876)	NS	Low	Consistent	Direct	Imprecise	Low
	Withdrawals – overall	4 RCT (1 IPD) (n=876)	Favors Placebo 37.2% vs. 26.8%, p=0.005	Low	Consistent	Direct	Imprecise	Low
	Withdrawals – adverse events	4 RCT (1 IPD) (n=876)	Favors Placebo 6.04% vs. 2.84%, p=0.049	Low	Consistent	Direct	Imprecise	Low
Topiramate +mood stabilizer vs. placebo+mood stabilizer	Response 12 wks YMRS 12 wks CGI-S 12 wks Withdrawals	1 RCT (n=287)	See table above	Low	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: CGI= Clinical Global Impressions; CGI-S=Clinical Global Impressions, Severity Scale; IPD=Individual Patient Data; 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 G41Outcomes summary: topiramate for mania vs. active control

Drug	Study Comparison PMID	Responder/Remitter	Symptom	Function	Other	AE
Topiramate vs. lithium	Kushner, 2006¹⁶ Low 16411977	NR	YMRS Change 3 week Mean difference (top-lith) 6.14 (95% CI 3.94, 8.34) Favors Lithium p<0.001	NR	Weight 3 week Mean difference (top-lith) −1.82% (95% CI −2.90%, −0.74%) Favors Topiramate p<0.001 Overall Withdrawal Topiramte=47/226 Lithium=51/227 NS Withdrawal lack of effect Topiramate=23/226 Lithium=19/227 NS Withdrawal adverse events Topiramate=6/226 Lithium=17/227 Favors Topiramate p=.019	SAE Topiramate 3% Lithium 1.5%
Topiramate + risperidone vs. divalproex + risperidone	Bahk, 2005¹⁴ High 15610953	Response (YMRS decrease ≥50%) 15 weeks NS >70% responded overall Remission (YMRS≤12) 15 weeks NS >60% achieved remission	YMRS 6 weeks NS (Both groups improved statistically significantly)	CGI 6 weeks NS (Both groups improved statistically significantly)	BMI Divalproex 73% patients increase Topiramate 25% patients decreased Overall Withdrawal NS Withdrawals reasons not reported by group	Reported no SAEs EPS NS between groups (“about 1/3 of patients in both groups”)

: Abbreviations: AE=Adverse Events; BMI=Body Mass Index; CGI=Clinical Global Impressions; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CI=Confidence Interval; EPS=extrapyramidal symptoms; GAF=General Assessment of Functioning Scale; NR=not reported; NS=not significant; PMID=PubMed Identification Number; RR=Risk Ratio; SAE=Serious Adverse Events; SD=standard deviation; YMRS = Young Mania Rating Scale

Appendix Table G42Strength of evidence assessment: topiramate for mania vs. active control

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Topiramate vs. Lithium	YMRS 3 wks	2 RCTs (1 IPD) (n=453)	Favors Lithium Mean difference 6.14 (95% CI 3.94, 8.34)	Low	Consistent	Direct	Imprecise	Low
	Withdraw – overall, lack of effect	2 RCTs (1 IPD) (n=453)	NS	Low	Consistent	Direct	Imprecise	Low
	Withdraw – adverse events	2 RCTs (1 IPD) (n=453)	Favors Topiramate 2.65% vs. 7.49%, p=0.019	Low	Consistent	Direct	Imprecise	Low
Topiramate + risperidone vs. divalproex + risperidone	Remission 6 wks Response 6 wks YMRS 6 wks CGI 6 wks Withdrawals	1 RCT (n=74)	See table above	High	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: CGI= Clinical Global Impressions; CI=Confidence Interval; GAF=General Assessment of Functioning Scale; IPD=Individual Patient Data; 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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