Mood Stabilizers 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 FMood Stabilizers for Mania

Section 1. Carbamazepine

Appendix Table F1Characteristics of eligible studies: carbamazepine 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
Weisler, 20061 2 pooled RCTs Multisite 2 Continents Industry RoB High 16529527 (pooled 15766298 and 15119909)	N = 443 Mean Age 38 Female 38% White 59% BP I 100% Inpatient or Outpatient	Manic/Mixed; YMRS ≥ 20 Taking Other Meds	Carbamazepine ER 200–1600 mg/day (642.6 mg/day average)	Placebo	3 weeks	YMRS CGI-S CGI-I HAM-D Withdrawal 46%
Vasudev, 20002 RCT Singlesite India Industry RoB Moderate 10867972	N = 30 Age NR Sex NR Race NR BP I 100% Outpatient	Mania; DSM-III criteria for BP diagnosis Substance Abuse Neurological Disorders Taking other meds Pregnant/Nursing	Carbamazepine 800–1600 mg/day (22.05 mg/kg/day)	Valproate 800–2200 mg/day (22.9 mg/kg/day)	4 weeks	Response (50% decrease in YMRS) YMRS Withdrawal 20%
Small, 19913 RCT Singlesite US Government RoB High 1929761	N = 48 Mean Age 39 Female 38% White 59% BP I 100% Inpatient	Manic/Mixed; YMRS ≥ 20 First Manic Episode Substance Abuse Other Mental Health	Carbamazepine 700 mg/day-1052 mg/day (high and low weekly mean dose) (950.8 mg/day mean weekly dose)	Lithium 1035–1278 mg/day (high and low mean dose) (1207.5 mean weekly dose)	8 weeks	SDMS-D SDMS-M YMRS GAS CGI-I BCL Withdrawal 42%
Lerer, 19874 RCT Singlesite US Industry RoB High 3546274	N = 34 Mean Age 41 Female 54% Race NR BP I 100% Inpatient	Manic Neurological Disorders	Carbamazepine 600–2600 mg/day (1250 mg/day mean of the reported weekly median)	Lithium 900–3900 mg/day (1650 mg/day mean of the reported weekly median)	4 weeks	Response (CGI change 2+) CGI Withdrawal 18%

: Abbreviations: AE=Adverse Events; AIMS=Abnormal Involuntary Movement Scale; BAS=Behavioral Approach System; BCL= Shopsin-Gershon Social Behavior Checklist; BIS-11=Barratt Impulsiveness Scale; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; C=Comparision; CGI=Clinical Global Impressions Scale; CGI-BP =Clinical Global Impressions Scale for Bipolar Disorder; CGI-I= Clinical Global Impressions-Improvement; CGI-S=Clinical Global Impressions, Severity Scale; DSM=Diagnostic and Statistical Manual of Mental Disorders; DSM-IV= Diagnostic and statistical manual, 4^th edition; DSS=Depressive Syndrome Scale; ER=extended release; GAF=General Assessment of Functioning Scale; GAS= Global Assessment Scale; HAM-D=Hamilton Scale for Depression; LIFE-RIFT= Range of Impaired Functioning Tool; MADRS=Montgomery-Asberg Depression Rating Scale; MSS=Manic Syndrome Scale; NOS=not otherwise specified; NR=not reported; PMID=PubMed Identification Number; RCT=randomized controlled trial; ROB=risk of bias; SADS-C=Schedule for Affective Disorders and Schizophrenia Change Version; SAS=Simpson Angus Scale; SDMS=Symptoms of Depression and Mania Scale; YMRS = Young Mania Rating Scale

Appendix Table F2Summary risk of bias assessments: carbamazepine for acute mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Carbamazepine	Weisler, 2006¹ Industry 16529527	High	Large dropout rates (46%) with randomization and blinding not described.
	Vasudev, 2000² Industry 10867972	Moderate	Protection of allocation not described, but blinding and randomization are well addressed as are other aspects of the paper. Withdrawal 20%.
	Small, 1991³ Government 1929761	High	Randomization procedure and allocation masking not described. 42% dropout.
	Lerer, 1987⁴ Industry 3546274	High	The researcher only included in the analysis those who completed the study. This is likely to bias the results of the Lithium group who lost roughly 1/4 of the study population during the four weeks. Randomization procedure and allocation masking not described. 18% dropout.

: Abbreviations: PMID=PubMed Identification Number

Appendix Table F3Outcomes summary: carbamezepine versus placebo for acute mania

Drug	Study PMID	Responder/Remitter	Symptom	Function	Other	AE
Carbamazepine vs. placebo	Weisler, 2006¹ 16529527 2 pooled RCTs (15766298 and 15119909) High	Responders (>50% decrease YMRS) 3 weeks Favors carbamazepine Carbamazepine 52% Placebo 26% p<0.0001	YMRS decrease 3 weeks Favors carbamazepine Carbamazepine 12.3 Placebo 6.2 p<0.0001 HAM-D decrease 3 weeks Favors carbamazepine Carbamazepine 2.9 Placebo 1.3 p=0.01	CGI-S increase 3 weeks Favors carbamazepine Carbamazepine 1.2 Placebo 0.5 p<0.0001 CGI-I improvement 3 weeks Favors carbamazepine Carbamazepine 55.6% Placebo 28.4% p<0.0001	Overall Withdrawal Carbamazepine 93/223 Placebo 110/220 NS Withdrawal lack of effect Carbamazepine 22/223 Placebo 49/220 Favors Carbamazepine Withdrawal adverse events Carbamazepine 24/223 Placebo 12/220 NR (EPC calculated favors carbamazepine) BMI Change Favors placebo ≥7% gain Carbamazepine 5.3% Placebo 1% p=0.011	SAE (from original studies) Carbamazepine: 8 patients Placebo: 10 patients Severe Rash: 11 carbamazepine patient 1 placebo patient attempted suicide

: Abbreviations: AE=Adverse Effects; BMI=Body Mass Index; CGI= Clinical Global Impressions; CGI-BP =Clinical Global Impressions Scale for Bipolar Disorder; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-I= Clinical Global Impressions-Improvement; CGI-S=CGI-Severity; CI= Confidence Interval; EPS=Extrapyramidal Side Effects; GAS= Global Assessment Scale; HAM-D=Hamilton Scale for Depression; MADRS=Montgomery-Asberg Depression Rating Scale; NR=not reported; NS=not significant; OPT=Optimalized Personalized Treatment; OR=Odds Ratio; PMID=PubMed Identification Number; RCT=randomized controlled trial; SAE= Serious Adverse Events; SD=Standard Deviation; SE=Standard Error; YMRS = Young Mania Rating Scale

Appendix Table F4Strength of evidence assessment: carbamezepine versus placebo for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Carbamazepine vs. placebo	Response YMRS CGI Withdrawals	1 RCT + 1 IPD (n=443)	See table above	High	Consistent (based on original RCTs)	Direct	Imprecise	Insufficient

: Abbreviations: AE=Adverse Events; CGI= Clinical Global Impressions; CI=Confidence Interval; IPD=Individual patient data; MADRS=Montgomery-Asberg Depression Rating Scale; MD=Mean Difference; 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 F5Outcomes summary: carbamezapine versus active comparator for acute mania

Drug	Study PMID	Responder/Remitter	Symptom	Function	Other	AE
Carbamazepine vs. lithium	Small, 1991³ 1929761 High	NR	YMRS 8 weeks Carbamazepine −8.5 Lithium −9.7 4% difference between groups HAM-D 8 weeks Carbamazepine −2.5 Lithium 0.5 10% difference between groups SDMS-D 8 weeks Carbamazepine 0 Lithium 0.6 18% difference between groups SDMS-M 8 weeks Carbamazepine −3.4 Lithium −3.3 1% difference between groups	CGI-I 8 weeks Carbamazepine −0.9 Lithium 1.0 1% difference between groups GAS 8 weeks Carbamazepine 11.7 Lithium 11.8 3% difference between groups	Overall Withdrawal Carbamazepine 16/24 Lithium 16/24 NS	SAE None
Carbamazepine vs. lithium	Lerer, 1987⁴ 3546274 High	Response (CGI change 2+) 4 weeks Favors lithium Carbamazepine 4/14 Lithium 11/14 p<0.05	NR	CGI Carbamazepine Baseline 5.6 (8.2) 4 weeks 4.1 (1.51) Lithium Baseline 5.7(0.88) 4 weeks 3.1(1.5) ANOVA group effect NS	Overall Withdrawal Carbamazepine 1/15 Lithium 4/19 NR Withdrawal adverse events Carbamazepine 1/15 Lithium 2/19 NR	SAE Carbamazepine 4/15 Lithium 1/19
Carbamazepine vs. valproate	Vasudev, 2000² 10867972 Moderate	Response (50% decrease in YMRS) 4 weeks Carbamazepine 8/15 Valproic acid 11/15 NS	NR	NR	Overall Withdrawal Carbamazepine 3/15 Valproic acid 3/15 NS	All AEs Carbamazepine 67% Valproic acid 17% Tremors Carbamazepine 25% Valproic acid 8%

: Abbreviations: AE=Adverse Effects; BPRS=Brief Psychiatric Rating Scale; CGI= Clinical Global Impressions Scale; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-I=Clinical Global Impressions Scale-Improvement; GAF=General Assessment of Functioning Scale; GAS=Global Assessment Scale; HAM-D=Hamilton Scale for Depression; MADRS=Montgomery-Asberg Syndrome Scale; MRS=mania rating scale; NR=not reported; NS=not significant; PMID=PubMed Identification Number; SAE= Serious Adverse Events; SD=standard deviation; SDMS-D=Symptoms of Depression and Mania Scale-Depression; YMRS = Young Mania Rating Scale

Appendix Table F6Strength of evidence assessment: carbamezapine versus active comparator for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Carbamazepine vs. lithium	Response YMRS CGI Withdrawals – overall Withdrawal – AEs	2 RCTs (n=82)	See table above	High	Consistent	Direct	Imprecise	Insufficient
Carbamazepine vs. valproate	Response Withdrawals – overall	1 RCT (n=30)	See table above	Moderate	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: AE=Adverse Event; CGI=Clinical Global Impressions Scale; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; n=number; 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. Divalproex/Valproate

Appendix Table F7Characteristics of eligible studies: divalproex 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
Tohen, 2008b⁵ RCT Multisite 3 Continents Industry RoB Low 19014751	N = 521 Mean Age 40 Female 49% Race NR Diagnosis NR Setting NR	Manic or Mixed Episode; YMRS 20–30 CGI-BP mania 3–4 Schizoaffective Other Mental Health Conditions Pregnant/Nursing	Divalproex 500–2500 mg/day	C1: Placebo C2: Olanzapine 5–20 mg/day	3 weeks	Response (YMRS reduction ≥ 50%) Time to response (days from baseline to ≥ 50% YMRS reduction) Remission (YMRS ≤ 12) Efficacy YMRS CGI (multiple subscales) MADRS Adverse events Extrapyramidal symptoms SAS BAS AIMS Withdrawal 26%
Bowden, 2006⁶ RCT Multisite US Industry RoB High 17107240	N = 364 Mean Age 38 Female 43% White 74% BP I 100% Inpatient (0–15 days) Outpatient (>15–21 days, subject to clinical criteria)	Mania; Mania Rating Scale (derived from SADS-C interview) ≥ 18 with at least 4 item scores >1. First Manic Episode; Schizoaffective; Substance Abuse; Other Mental Health Conditions; Taking other Medications;	Divalproex 85–125 microgram/ml (2961 mg/day average)	Placebo	3 weeks	Remission (YMRS ≤ 12) Response (50% decrease in YMRS) YMRS BIS MSS GAS DSS AEs Weight gain Withdrawal 45%
Xu, 2015⁷ 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	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%

: Abbreviations: AE=Adverse Events; AIMS=Abnormal Involuntary Movement Scale; BAS=Behavioral Approach System; BCL= Shopsin-Gershon Social Behavior Checklist; BIS-11=Barratt Impulsiveness Scale; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; C=Comparision; CGI=Clinical Global Impressions Scale; CGI-BP =Clinical Global Impressions Scale for Bipolar Disorder; CGI-I= Clinical Global Impressions-Improvement; CGI-S=Clinical Global Impressions, Severity Scale; DSM=Diagnostic and Statistical Manual of Mental Disorders; DSM-IV= Diagnostic and statistical manual, 4^th edition; DSS=Depressive Syndrome Scale; ER=extended release; GAF=General Assessment of Functioning Scale; GAS= Global Assessment Scale; HAM-D=Hamilton Scale for Depression; LIFE-RIFT= Range of Impaired Functioning Tool; MADRS=Montgomery-Asberg Depression Rating Scale; MSS=Manic Syndrome Scale; NOS=not otherwise specified; NR=not reported; PMID=PubMed Identification Number; RCT=randomized controlled trial; ROB=risk of bias; SADS-C=Schedule for Affective Disorders and Schizophrenia Change Version; SAS=Simpson Angus Scale; SDMS=Symptoms of Depression and Mania Scale; YMRS = Young Mania Rating Scale

Appendix Table F8Summary risk of bias assessments: dival/valproate for acute mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Divalproex/Valproate	Tohen, 2008⁵ Industry 19014751	Low	No sources of bias identified. 26% dropout at 3 weeks.
	Bowden, 2006⁶ Industry 17107240	High	Randomization and allocation procedures not described. Author notes, “We plan to report in a separate article a detailed exploration of the site-related differences and the implications for study design and execution” This statement infers that there is a difference caused by site that is not addressed or controlled for in the paper. 45% dropout.
	Xu, 2015⁷ Government 26060401	Low	Well-constructed, described, and reported study. 5% dropout.

: Abbreviations: PMID=PubMed Identification Number

Appendix Table F9Outcomes summary: divalproex/valproate versus placebo for acute mania

Drug	Study PMID	Responder/Remitter	Symptom	Function	Other	AE
Divalproex vs. placebo	Bowden, 2006⁶ 17107240 High	Response 3 weeks Favors divalproex Divalproex 48% Placebo 34% p=0.012 Remission 3 weeks Favors divalproex Divalproex 48% Placebo 35% p=0.015	MRS Change 3 weeks Favors divalproex Divalproex −11.5 Placebo −9.0 p=0.013	GAS 3 weeks NS	Overall Withdrawal Divalproex 108/187 Placebo 92/177 NS Withdrawal lack of effect Divalproes 24/187 Placebo 46/177 Favors Divalproex p=0.001 Withdrawal adverse events Divalproex 19/187 Placebo 5/177 Favors Placebo p=0.003	Serious Adverse Events 3 weeks 1 in divalproex 0 in placebo Deaths 3 weeks 0 in both arms
Divalproex vs. placebo	Tohen, 2008⁵ 19014751 Low	Response 3 weeks Divalproex 40.3% Placebo 31.3% NS Remission 3 weeks Divalproex 40.3% Placebo 35.4% NS	YMRS Change 3 weeks Divalproex −8.2 (SE 0.62) Placebo −7.4 (SE 0.80) NS	CGI Overall Change 3 weeks Divalproex −0.6 (SE 0.08) Placebo −0.5 (SE 0.10) NS CGI Mania Change 3 weeks Divalproex −0.8 (SE 0.08) Placebo −0.7 (SE 0.11) NS CGI Depression Change 3 weeks Divalproex −0.2 (SE 0.07) Placebo −0.1 (SE 0.09) NS	Withdrawal 3 weeks Overall: 25.5% Efficacy: 2.0% AEs: 2.3%	Serious Adverse Events 3 weeks 1 in divalproex 1 in placebo
Valproate adjunctive vs. placebo or no placebo	Xu, 2015⁷ 26060401 Low	NR	YMRS 3 weeks Favors Valproate % Reduction (SD) Olanzapine+Valporate= 86.5% (8.9%) Olanzapine= 75.2% (15.1%) P<0.01 CGI-BP 3 weeks Favors Valproate p<0.01	NR	Overall Withdrawal 3 weeks NS Olanzapine + Valporate = 2/40 Olanzapine=1/40 Withdrawal due to AEs 3 weeks NS Olanzapine+Valporate=2/40 Olanzapine=1/40 Withdrawal, Lack of Efficacy 3 weeks NS Olanzapine+Valporate=0/40 Olanzapine=0/40	Severe Harms 3 weeks NS Olanzapine+Valporate=1/38 Olanzapine=0/39 Normalized Weight Change 3 weeks Olanzapine+Valporate=31/38 Olanzapine=29/39 Emergent Mood Episodes 3 weeks NS Olanzapine+Valporate=0/38 Olanzapine=0/39

: Abbreviations: AE=Adverse Effects; BMI=Body Mass Index; CGI= Clinical Global Impressions; CGI-BP =Clinical Global Impressions Scale for Bipolar Disorder; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-I= Clinical Global Impressions-Improvement; CGI-S=CGI-Severity; CI= Confidence Interval; EPS=Extrapyramidal Side Effects; GAS= Global Assessment Scale; HAM-D=Hamilton Scale for Depression; MADRS=Montgomery-Asberg Depression Rating Scale; NR=not reported; NS=not significant; OPT=Optimalized Personalized Treatment; OR=Odds Ratio; PMID=PubMed Identification Number; RCT=randomized controlled trial; SAE= Serious Adverse Events; SD=Standard Deviation; SE=Standard Error; YMRS = Young Mania Rating Scale

Appendix Table F10Strength of evidence assessment: divalproex/valproate versus placebo for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Divalproex vs. placebo	Relapse Remission YMRS CGI Withdrawals	2 RCTs (n=670)	See table above	Moderate	Inconsistent	Direct	Imprecise	Insufficient
Valproate vs. no placebo	YMRS CGI Withdrawals	1 RCT (n=79)	See table above	Low	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: AE=Adverse Events; CGI= Clinical Global Impressions; CI=Confidence Interval; IPD=Individual patient data; MADRS=Montgomery-Asberg Depression Rating Scale; MD=Mean Difference; 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. Lamotrigine

Appendix Table F11Characteristics of eligible studies: lamotrigine 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
Ichim, 2000⁸ RCT Singlesite South Africa Industry RoB Moderate 10798820	N=30 Mean Age 33 Female 47% Race NR BP I 100% Inpatient	Mania Substance Abuse Taking Other Meds Pregnant/Nursing Labs/Other Conditions	Lamotrigine Week 1 25mg/day, Week 2 50mg/day, Week 3 100mg/day	Lithium 400mg twice/daily	4 weeks	YMRS BPRS CGI GAF Withdrawal 17%

: Abbreviations: AE=Adverse Events; AIMS=Abnormal Involuntary Movement Scale; BAS=Behavioral Approach System; BCL= Shopsin-Gershon Social Behavior Checklist; BIS-11=Barratt Impulsiveness Scale; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; C=Comparision; CGI=Clinical Global Impressions Scale; CGI-BP =Clinical Global Impressions Scale for Bipolar Disorder; CGI-I= Clinical Global Impressions-Improvement; CGI-S=Clinical Global Impressions, Severity Scale; DSM=Diagnostic and Statistical Manual of Mental Disorders; DSM-IV= Diagnostic and statistical manual, 4^th edition; DSS=Depressive Syndrome Scale; ER=extended release; GAF=General Assessment of Functioning Scale; GAS= Global Assessment Scale; HAM-D=Hamilton Scale for Depression; LIFE-RIFT= Range of Impaired Functioning Tool; MADRS=Montgomery-Asberg Depression Rating Scale; MSS=Manic Syndrome Scale; NOS=not otherwise specified; NR=not reported; PMID=PubMed Identification Number; RCT=randomized controlled trial; ROB=risk of bias; SADS-C=Schedule for Affective Disorders and Schizophrenia Change Version; SAS=Simpson Angus Scale; SDMS=Symptoms of Depression and Mania Scale; YMRS = Young Mania Rating Scale

Appendix Table F12Summary risk of bias assessments: lamotrigine for acute mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Lamotrigine	Ichim, 20008 Industry 10798820	Moderate	Randomization and blinding procedures not described. Initial difference between the two groups identified on duration since index episode before hospitalization.

: Abbreviations: PMID=PubMed Identification Number

Appendix Table F13Outcomes summary: lamotrigine versus active comparator for acute mania

Drug	Study PMID	Responder/Remitter	Symptom	Function	Other	AE
Lamotrigine vs. Lithium	Ichim, 2000⁸ Moderate 10798820	Response 4 weeks NS Lamotrigine=8/15 Lithium=9/15	YMRS 4 weeks NS Lamotrigine=14.3 Lithium=13.2 BPRS 4 weeks NS Lamotrigine=30.2 Lithium=28.2	CGI-Severity 4 weeks NS Lamotrigine=2.77 Lithium=2.87 CGI-Improvement 4 weeks NS GAF 4 weeks NS Lamotrigine=55.7 Lithium=56.2	Overall Withdrawal 4 weeks NS 17% Lamotrigine=2/15 Lithium=3/15	Serious AEs 4 weeks No serious AEs reported in either group and no rashes were reported in the lamotrigine group.

: Abbreviations: AE=Adverse Effects; BPRS=Brief Psychiatric Rating Scale; CGI= Clinical Global Impressions Scale; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-I=Clinical Global Impressions Scale-Improvement; GAF=General Assessment of Functioning Scale; GAS=Global Assessment Scale; HAM-D=Hamilton Scale for Depression; MADRS=Montgomery-Asberg Syndrome Scale; MRS=mania rating scale; NR=not reported; NS=not significant; PMID=PubMed Identification Number; SAE= Serious Adverse Events; SD=standard deviation; SDMS-D=Symptoms of Depression and Mania Scale-Depression; YMRS = Young Mania Rating Scale

Appendix Table F14Strength of evidence assessment: lamotrigine versus active comparator for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Lamotrigine vs. lithium	Response Withdrawals – overall	1 RCT (n=30)	See table above	Moderate	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: AE=Adverse Event; CGI=Clinical Global Impressions Scale; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; n=number; 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. Lithium

Appendix Table F15Characteristics of eligible studies: lithium 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
Kushner, 2006⁹ RCT Multisite 4 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)	Mania; YMRS ≥ 20 Schizoaffective; Substance Abuse; Other Mental Health Conditions; Taking Other Medications;	Topiramate 400mg/day (mean 313mg/day) (only 400 mg/day arms were common across pooled studies)	C1: Placebo n=427 C2: Lithium 300–1800 mg/day (0.8–1.2mEq/L) n=227	3 weeks	YMRS Weight BPRS CGI-S GAS Withdrawal 26%
Bowden, 2005¹⁰ RCT Multisite 2 Continents Industry RoB High 15669897	N=302 Mean Age 39 Female 42% Race NR BP I 100% Inpatient (week 1) Outpatient (weeks 2–12, subject to inspector discretion)	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 Use; Taking other medications; Pregnant/Nursing; Labs/Other Conditions	Lithium 0.6–1.4 mEq/L (mean 0.80 mEq/L)	C1:Placebo C2: Quetiapine 100–800mg/day	12 weeks	CGI-BP-S GAS Remission YMRS ≤12) Response (≥50% YMRS decrease) Withdrawal 43%
Segal, 1998¹¹ 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 Medications; Pregnant/Nursing; Abnormal Lab Results	Lithium 0.6–1.2 mmol/L (Mean 0.72 mmol/L)	C1: Placebo C2: Haloperidol 10 mg/day	4 weeks	BPRS CGI Unknown Scale - Not reported whether global improvement or severity scale is being reported GAF MRS Seclusion – Hours Seclusion - Proportion of patients needing SAS Withdrawal 13%
Bowden, 2010¹² RCT Multisite 2 Continents Industry RoB Moderate 20101186	N = 270 Mean Age 39 Female 59% Race NR BP I 100% Inpatient and Outpatient	Mania; YMRS ≥ 18 First Manic Episode Substand Abuse Pregnant/Nursing Labs/Other Conditions Other Mental Health	Lithium 0.6–1.2 mmol/L (mean 969 mg/day)	Valproate 70–125 mcg/ml (mean 1394 mg/day)	12 weeks	CGI-BP-S Remission (YMRS ≤12 and decrease in CGI-BP ≥ 2) Remission (YMRS ≤ 12 and no increase in MADRS total score OR YMRS ≤ 12 and CGI ≤ 2 points) Response (improvement in YMRS ≥30%) YMRS Withdrawal 28%

: Abbreviations: AE=Adverse Events; AIMS=Abnormal Involuntary Movement Scale; BAS=Behavioral Approach System; BCL= Shopsin-Gershon Social Behavior Checklist; BIS-11=Barratt Impulsiveness Scale; BP=bipolar disorder; BPRS=Brief Psychiatric Rating Scale; C=Comparision; CGI=Clinical Global Impressions Scale; CGI-BP =Clinical Global Impressions Scale for Bipolar Disorder; CGI-I= Clinical Global Impressions-Improvement; CGI-S=Clinical Global Impressions, Severity Scale; DSM=Diagnostic and Statistical Manual of Mental Disorders; DSM-IV= Diagnostic and statistical manual, 4^th edition; DSS=Depressive Syndrome Scale; ER=extended release; GAF=General Assessment of Functioning Scale; GAS= Global Assessment Scale; HAM-D=Hamilton Scale for Depression; LIFE-RIFT= Range of Impaired Functioning Tool; MADRS=Montgomery-Asberg Depression Rating Scale; MSS=Manic Syndrome Scale; NOS=not otherwise specified; NR=not reported; PMID=PubMed Identification Number; RCT=randomized controlled trial; ROB=risk of bias; SADS-C=Schedule for Affective Disorders and Schizophrenia Change Version; SAS=Simpson Angus Scale; SDMS=Symptoms of Depression and Mania Scale; YMRS = Young Mania Rating Scale

Appendix Table F16Summary risk of bias assessments: lithium for acute mania

Drug	Study Funding Source PMID	Overall Risk of Bias Assessment	Rationale
Lithium	Bowden, 2010¹² Industry 20101186	Moderate	Randomization procedure not described, patients and raters may not be blinded. 28% dropout.
	Kushner, 2006⁹ Industry 16411977	Low	No sources of bias identified
	Bowden, 2005¹⁰ Industry 15669897	High	Randomization and blinding not described. Overall dropout of 43%.
	Segal, 1998¹¹ Industry/University 9617509	Moderate	Noted ‘randomly and assigned consecutively to treatment with…” which is a pseudorandom assignment technique. Blinding not described.

: Abbreviations: PMID=PubMed Identification Number

Mood Stabilizer 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 F1Lithium vs. placebo – remission

Appendix Figure F2Lithium vs. placebo – response

Appendix Figure F3Lithium vs. placebo – YMRS

Appendix Figure F4Lithium vs. placebo – overall withdrawal

Appendix Figure F5Lithium vs. placebo – withdrawal lack of efficacy

Appendix Figure F6Lithium vs. placebo – withdrawal adverse events

Appendix Table F17Outcomes summary: lithium versus placebo for acute mania

Drug	Study PMID	Responder/Remitter	Symptom	Function	Other	AE
Lithium vs. placebo	Bowden, 2005¹⁰ 15669897 Moderate	Response See forest plot F1 above Remission See forest plot F2 above	YMRS See forest plot F3 above	CGI-BP 12 weeks Favors Lithium Lithium= −2.2 Placebo=−0.9 Difference in Difference (SD)= 1.3 (0.38) p<0.001	Overall Withdrawal See forest plot F4 above Withdrawal due to Lack of Efficacy 12 weeks Favors Lithium Lithium= 12/98 Placebo=38/97 OR=0.22 (95% CI 0.10, 0.45) p<0.0001 Withdrawal due to AEs 12 weeks NS Lithium= 6/98 Placebo=4/97 OR=1.49 (95% CI 0.40, 6.26) p=0.75	EPS 12 weeks Lithium= 21/98* Placebo=35/97 *May be more cases, exact number NR Emergent Depression 12 weeks Lithium= 8/95 Placebo=3/97 Akathisia 12 weeks Lithium= 3/98 Placebo=6/97
Lithium vs. placebo	Kushner, 2006⁹ 16411977 Low	Response See forest plot F1 above Remission See forest plot F2 above	YMRS See forest plot F3 above	NR	Overall Withdrawal See forest plot F4 above Withdrawal Lack of Efficacy See forest plot F5 above Withdrawal due to AEs See forest plot F6 above	Severe AEs 3 weeks (Placebo) 12 weeks (Lithium) Lithium= 4/227 Placebo=9/427 Emergent Depression 3 weeks (Placebo) 12 weeks (Lithium) Lithium= 16/227 Placebo=51/427 Emergent Depression 12 weeks (Lithium) 3 weeks (Placebo) 3 cases of suicidal ideation in placebo group.

: Abbreviations: AE=Adverse Effects; BMI=Body Mass Index; CGI= Clinical Global Impressions; CGI-BP =Clinical Global Impressions Scale for Bipolar Disorder; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-I= Clinical Global Impressions-Improvement; CGI-S=CGI-Severity; CI= Confidence Interval; EPS=Extrapyramidal Side Effects; GAS= Global Assessment Scale; HAM-D=Hamilton Scale for Depression; MADRS=Montgomery-Asberg Depression Rating Scale; NR=not reported; NS=not significant; OPT=Optimalized Personalized Treatment; OR=Odds Ratio; PMID=PubMed Identification Number; RCT=randomized controlled trial; SAE= Serious Adverse Events; SD=Standard Deviation; SE=Standard Error; YMRS = Young Mania Rating Scale

Appendix Table F18Strength of evidence assessment: lithium versus placebo for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Lithium vs. placebo	Remission 3 wks Response 3 wks	1 RCT + 1 IPD (n=325)	Favors Lithium	Moderate	Consistent	Direct	Imprecise	Low
	YMRS 3 wks	3 RCTs (n=325)	Favors Lithium MD 5.81 (95% CI 2.21, 9.4)	Moderate	Consistent	Direct	Imprecise	Low
	Withdrawal – Overall 3 wks	3 RCTs (n=325)	NS	Moderate	Consistent	Direct	Imprecise	Low
	Withdrawal – Lack of Efficacy, AE	1 IPD (n=450)	NS	Moderate	Consistent	Direct	Imprecise	Low
	CGI	1 RCT (n=193)	See table above	Moderate	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: AE=Adverse Events; CGI= Clinical Global Impressions; CI=Confidence Interval; IPD=Individual patient data; MADRS=Montgomery-Asberg Depression Rating Scale; MD=Mean Difference; 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 F19Outcomes summary: lithium active comparator for acute mania

Drug	Study PMID	Responder/Remitter	Symptom	Function	Other	AE
Lithium vs. haloperidol	Segal, 1998¹¹ 9617509 Moderate	NR	MRS 4 weeks NS Lithium= −19.3 Haloperidol=−19.9	CGI-BP 4 weeks NS No additional data reported	Overall Withdrawal 4 weeks NS Lithium= 1/15 Haloperidol=3/15 p=0.06	NR
Lithium vs. valproate	Bowden, 2010¹² 20101186 Moderate	Response 12 weeks Valproate 79.5% Lithium 72.6% NS Remission (YMRS/MADRS) 12 weeks Valproate 71.3% Lithium 65.9% NS Remission (YMRS/CGI) 12 weeks Favors valproate Valproate 71.9% Lithium 58.5% p=0.025	YMRS Change (90% CI) 12 weeks Valproate −17.3 (9.4) Lithium −15.8 (5.3) NS	CGI-BP-S Change 12 weeks Valproate −2.1 (1.4) Lithium −2.3 (1.3) NS	Overall Withdrawal Lithium 38/135 Valproate 34/122 Withdrawal Lack of efficacy Lithium 13/135 Valproate 13/122 Withdrawal AE Lithium 9/138 Valproate 8/122	Serious Adverse Events 12 weeks 10 in valproate 5 in lithium Weight gain >7% Lithium 9% Valproate 7%

: Abbreviations: AE=Adverse Effects; BPRS=Brief Psychiatric Rating Scale; CGI= Clinical Global Impressions Scale; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; CGI-I=Clinical Global Impressions Scale-Improvement; GAF=General Assessment of Functioning Scale; GAS=Global Assessment Scale; HAM-D=Hamilton Scale for Depression; MADRS=Montgomery-Asberg Syndrome Scale; MRS=mania rating scale; NR=not reported; NS=not significant; PMID=PubMed Identification Number; SAE= Serious Adverse Events; SD=standard deviation; SDMS-D=Symptoms of Depression and Mania Scale-Depression; YMRS = Young Mania Rating Scale

Appendix Table F20Strength of evidence assessment: lithium versus active comparator for acute mania

Comparison	Outcome	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Lithium vs. haloperidol	YMRS CGI	1 RCT (n=30)	See table above	Moderate	Unknown	Direct	Imprecise	Insufficient
Lithium vs. divalproex	Response Remission YMRS CGI-BP-S Withdrawals	1 RCT (n=270)	See table above	Moderate	Unknown	Direct	Imprecise	Insufficient

: Abbreviations: AE=Adverse Event; CGI=Clinical Global Impressions Scale; CGI-BP-S=Clinical Global Impressions, Bipolar, Severity Scale; n=number; 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.

References for Appendix F

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