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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.)
Section 1. Sertraline vs. Lithium vs. Lithium + Sertraline
Appendix Table H1Characteristics of eligible studies: sertraline for depression
| 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 | Followup Duration | Outcomes Reported Withdrawal (%) at endpoint |
|---|---|---|---|---|---|---|
| Altshuler, 20171 RCT Multisite US Government RoB High 28135846 | N=142 Mean Age 39 Female 54% White 97% BP II 100% Outpatient | BPII; current major depressive episode. IDS-C≥22; CGI-BP≥3 on depression subscale; YMRS≤8; CGI-BP=1 on mania severity subscale Substance Abuse Other Mental Health (Nonresponsive to Lithium or Sertraline) | Sertraline target 100 mg/day | C1: Lithium target 900 mg/day C2: Sertraline+ Lithium target 100 mg/day+900 mg/day | 16 weeks | Switch to hypomania or mania (YMRS≥14 + CGI-BP≥4) Treatment response (decrease of ≥50% IDS-C OR decrease ≥2 points CGI-BP depression) Adverse Events Withdrawal 56% (Non-relapse withdrawal 32%) |
Abbreviations: BP=bipolar disorder; C=Comparison; CGI=Clinical Global Impressions Scale; CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; DSM-IV=Diagnostic and Statistical Manual of Mental Disorders, 4th Revision; GAF=General Assessment of Functioning Scale; HAM-D=Hamilton Scale for Depression; HSRD=Hamilton Rating Scale for Depression; IDS-C=Inventory for Depressive Symptoms(Clinician-Rated); MADRS=Montgomery-Asberg Depression Rating Scale; NOS=not otherwise specified; NR=not reported; PMID=PubMed Identification Number; RCT=randomized controlled trial; ROB=risk of bias; SRS=symptom rating scale; SUM-D=Symptom Subscale for Depression; SUM-ME=Symptom Subscale for Mood Elevation; YMRS = Young Mania Rating Scale
Appendix Table H2Summary risk of bias assessments: sertraline for depression
| Drug | Study Funding Source PMID | Overall Risk of Bias Assessment | Rationale |
|---|---|---|---|
| Sertraline vs. Lihtium vs. Lithium + Sertraline | Altshuler, 20171 Government 28135846 | High | Overall attrition 56%; only time to relapse or withdrawal outcomes used. Block randomization. Allocation concealment described. Blinded assessors; unblinded treatment physicians in communication with blinded physician. No discussion of missing data approaches for generalized mixed modeling. Log rank test. |
Abbreviations: PMID=PubMed Identification Number; YMRS=Young Mania Rating Scale
Appendix Table H3Outcomes summary: sertraline for depression
| Drug | Study PMID | Responder/Remitter | Symptom | Function | Other | AE |
|---|---|---|---|---|---|---|
| Sertraline vs. Lihtium vs. Lithium + Sertraline | Altshuler, 20171 28135846 | Treatment response 16 weeks 62.7% overall NS across groups | NA | NA | Switching 16 weeks 14% overall NS across groups | NR |
Abbreviations: AE=Adverse Events; CGI=Clinical Global Impressions Scale; HAM-D=Hamilton Scale for Depression; MID=minimally important difference; NA=Not applicable; NR=not reported; NS=not significant; PMID=PubMed Identification Number; SAE=Serious Adverse Events; YMRS =Young Mania Rating Scale
Appendix Table H4Strength of evidence assessment: sertraline for depression
| Comparison | Outcome | # Studies/Design (n analyzed) | Finding or Summary Statistic | Study Limitations | Consistency | Directness | Precision | Overall Grade/Conclusion |
|---|---|---|---|---|---|---|---|---|
| Sertraline vs. Lihtium vs. Lithium + Sertraline | Response16 wks Switching 16 wks | 1 RCT (n=142) | See table above | High | Unknown | Direct | Imprecise | Insufficient |
Abbreviations: CGI= Clinical Global Impressions; HAM-D=Hamilton Scale for Depression; n=number of subjects; RCT=randomized controlled trial
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. Venlafaxine vs. Lithium
Appendix Table H5Characteristics of eligible studies: venlafaxine for depression
| 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 | Followup Duration | Outcomes Reported Withdrawal (%) at endpoint |
|---|---|---|---|---|---|---|
| Amsterdam, 20162 RCT Singlesite US Government RoB Moderate 26892848 268037643 | N=129 Mean Age 43 Female 57% White 73% BP II 100% Outpatient | BPII; current major depressive episode. HAM-D≥16 Substance Abuse Other Mental Health Pregnant/Nursing Taking Other Meds Labs/Other Conditions (Nonresponsive to Venlafaxine or Lithium) | Venlafaxine max 375 mg/day min 75 mg/day | Lithium serum level 0.8 to 1.5 mmol/L | 12 weeks | Response (HSRD reduction ≥50% plus CGI/S=1) Remission (HSRD≤8 plus CGI/S=1 or 2) HSRD CGI/SRS Adverse Events Withdrawal 29% |
| Amsterdam, 20084,
5 Open label RCT Singlesite US Government RoB High 18344727 184862355 | N=83 Mean Age 37 Female 57% White 82% BP II 100% Outpatient | BPII; current major depressive episode. HAM-D≥18 Substance Abuse Other Mental Health Pregnant/Nursing Taking Other Meds Labs/Other Conditions (Nonresponsive to Venlafaxine or Lithium) | Venlafaxine max 375 mg/day min 75 mg/day | Lithium serum level 0.8 to 1.5 mmol/L | 12 weeks | Response (HAM-D reduction ≥50%) Remission (HAM-D final ≤8) HAM-D YMRS CGI Withdrawal 40% |
Abbreviations: BP=bipolar disorder; C=Comparison; CGI=Clinical Global Impressions Scale; CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; DSM-IV=Diagnostic and Statistical Manual of Mental Disorders, 4th Revision; GAF=General Assessment of Functioning Scale; HAM-D=Hamilton Scale for Depression; HSRD=Hamilton Rating Scale for Depression; IDS-C=Inventory for Depressive Symptoms(Clinician-Rated); MADRS=Montgomery-Asberg Depression Rating Scale; NOS=not otherwise specified; NR=not reported; PMID=PubMed Identification Number; RCT=randomized controlled trial; ROB=risk of bias; SRS=symptom rating scale; SUM-D=Symptom Subscale for Depression; SUM-ME=Symptom Subscale for Mood Elevation; YMRS = Young Mania Rating Scale
Appendix Table H6Summary risk of bias assessments: venlafaxine for depression
| Drug | Study Funding Source PMID | Overall Risk of Bias Assessment | Rationale |
|---|---|---|---|
| Venlafaxine vs. Lithium | Amsterdam, 20162 Government 26892848 268037643 | Moderate | Overall attrition 29%. Differential attrition between arms. No discussion of missing data approaches for Fischers test or generalized estimating equations. |
| Amsterdam, 20084Government 18344727 184862355 | High | Open-label study. Attrition 40%. Differential attrition. |
Abbreviations: PMID=PubMed Identification Number; YMRS=Young Mania Rating Scale
Appendix Table H7Outcomes summary: venlafaxine for depression
| Drug | Study PMID | Responder/Remitter | Symptom | Function | Other | AE |
|---|---|---|---|---|---|---|
| Venlafaxine vs. Lithium | Amsterdam, 20162 26892848 268037643 | Remission 12 weeks Venlafaxine 38/65 (58.5%) Lithium 18/64 (28.1%) Favors Venlafaxine p=0.0007 Response 12 weeks Venlafaxine 44/65 (67.7%) Lithium 22/64 (34.4%) Favors Venlafaxine p=0.0002 | HAM-D 12 weeks Modeling Favors Venlafaxine p<0.0001 (Not interpretable to MID) | CGI/S 12 weeks Modeling Favors Venlafaxine p<0.0001 | Switching 12 weeks NS | Reported no serious adverse events |
| Amsterdam, 20084 18344727 184862355 | Remission 12 weeks Venlafaxine 28/43 (44.2%) Lithium 13/40 (7.5%) Favors Venlafaxine p=0.0005 Response 12 weeks Venlafaxine 26/43 (60.4%) Lithium 8/40 (20%) Favors Venlafaxine p=0.0005 | HAM-D 17 12 weeks Modeling Favors Venlafaxine −4.51 (−8.36 to −0.66) P=0.015 Less than MID of at least 27.1% improvement, or 14/52 | CGI/S 12 weeks Modeling Favors Venlafaxine p<0.009 | Switching 12 weeks NS | SAE 1 in lithium group (not described) NS for withdraw due to adverse event |
Abbreviations: AE=Adverse Events; CGI=Clinical Global Impressions Scale; HAM-D=Hamilton Scale for Depression; MID=minimally important difference; NA=Not applicable; NR=not reported; NS=not significant; PMID=PubMed Identification Number; SAE=Serious Adverse Events; YMRS =Young Mania Rating Scale
Appendix Table H8Strength of evidence assessment: venlafaxine for depression
| Comparison | Outcome | # Studies/Design (n analyzed) | Finding or Summary Statistic | Study Limitations | Consistency | Directness | Precision | Overall Grade/Conclusion |
|---|---|---|---|---|---|---|---|---|
| Venlafaxine vs. Lithium | Response 12 wks Remission 12 wks Ham-D 12 wks CGI/S 12 wks | 2 RCTs (n=212) | See table above | Moderate | Consistent | Direct | Imprecise | Insufficient (weighted toward single moderate rob study of 129) |
Abbreviations: CGI= Clinical Global Impressions; HAM-D=Hamilton Scale for Depression; n=number of subjects; RCT=randomized controlled trial
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. Memantine + Valproate vs. Placebo + Valproate
Appendix Table H9Characteristics of eligible studies: memantine for depression by year then first author
| Study, Year Design Location Funder Risk of Bias PMID | # Randomized Age (mean) Sex (% Female) Race (% White) Diagnosis (% BP I, II, NOS) Setting | Inclusions Key Exclusions | Intervention Dosage | Comparison Dosage | Followup Duration | Outcomes Reported Withdrawal (%) at endpoint |
|---|---|---|---|---|---|---|
| Lee, 20146,
7 RCT Multisite Asia Government RoB High 24103632/23870798 | N = 232 Mean Age 32 Female 49% Race NR BP II 100% Inpatient and/or Outpatient (NR) | Modified BPII (2-days hypomanic versus 4-days used in DSM-IV criteria); HAM-D≥18 Schizoaffective Substance abuse Other mental health Neurological disorders Taking other medications | Memantine 5 mg/daily + Valproate 500–1000 mg/day | Placebo + Valproate 500–1000 mg/day | 12 weeks | YMRS HAM-D Withdrawal 32% |
Abbreviations: BP=bipolar disorder; C=Comparison; CGI=Clinical Global Impressions Scale; CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; DSM-IV=Diagnostic and Statistical Manual of Mental Disorders, 4th Revision; GAF=General Assessment of Functioning Scale; HAM-D=Hamilton Scale for Depression; HSRD=Hamilton Rating Scale for Depression; IDS-C=Inventory for Depressive Symptoms(Clinician-Rated); MADRS=Montgomery-Asberg Depression Rating Scale; NOS=not otherwise specified; NR=not reported; PMID=PubMed Identification Number; RCT=randomized controlled trial; ROB=risk of bias; SRS=symptom rating scale; SUM-D=Symptom Subscale for Depression; SUM-ME=Symptom Subscale for Mood Elevation; YMRS = Young Mania Rating Scale
Appendix Table H10Summary risk of bias assessments: memantine for depression
| Drug | Study Funding Source PMID | Overall Risk of Bias Assessment | Rationale |
|---|---|---|---|
| Memantine + valproate vs. placebo + valproate | Lee, 20146, 7 Government 24103632 | High | Randomization and blinding procedures not described; Inpatient and outpatient settings of patients not described or included in analysis, creating a residual confounder; baseline YMRS score not balanced between arms and not included in modelling analysis; handling of attrition not described |
Abbreviations: PMID=PubMed Identification Number; YMRS=Young Mania Rating Scale
Appendix Table H11Outcomes summary: memantine for depression
| Drug | Study PMID | Responder/Remitter | Symptom | Function | Other | AE |
|---|---|---|---|---|---|---|
| Memantine + valproate vs. placebo + valproate | Lee, 20146,
7 24103632 | NR | HAM-D 12 week NS p=0.363 YMRS 12 week NS p=0.115 | NR | NR | NR |
Abbreviations: AE=Adverse Events; CGI=Clinical Global Impressions Scale; HAM-D=Hamilton Scale for Depression; MID=minimally important difference; NA=Not applicable; NR=not reported; NS=not significant; PMID=PubMed Identification Number; SAE=Serious Adverse Events; YMRS =Young Mania Rating Scale
Appendix Table H12Strength of evidence assessment: memantine for depression
| Comparison | Outcome | # Studies/Design (n analyzed) | Finding or Summary Statistic | Study Limitations | Consistency | Directness | Precision | Overall Grade/Conclusion |
|---|---|---|---|---|---|---|---|---|
| Memantine + valproate vs. placebo + valproate | HAM-D 12 wks | 1 RCT (n=232) | See table above | High | Unknown | Direct | Imprecise | Insufficient |
Abbreviations: CGI= Clinical Global Impressions; HAM-D=Hamilton Scale for Depression; n=number of subjects; RCT=randomized controlled trial
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. Lamotrigine + Mood Stabilizers vs. Placebo + Mood Stabilizers
Appendix Table H13Characteristics of eligible studies: lamotrigine for depression
| 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 | Followup Duration | Outcomes Reported Withdrawal (%) at endpoint |
|---|---|---|---|---|---|---|
| Kemp, 20128 RCT Single US Gov’t+nonprofit ROB Moderate 23107222 | N=49 Mean Age 50 Female 56% White 92% BP I 55% BP II 45% | BPI or II; rapid cycling in previous 12 months; MADRS≥20 Substance Abuse Other Mental Health Pregnant/Nursing Taking Other Meds (nonresponsive to lamotrigine previously) | Lamotrigine 15–200 mg/day + Lithium or divalproex | Placebo + Lithium or divalproex | 12 weeks | MADRS CGI-S YMRS Response (MADRS ≥50% decrease) Remission (MADRS≤10) Bimodal response (MADRS ≤19, YMRS≤12, GAF ≥51) Withdrawal 17% |
Abbreviations: BP=bipolar disorder; C=Comparison; CGI=Clinical Global Impressions Scale; CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; DSM-IV=Diagnostic and Statistical Manual of Mental Disorders, 4th Revision; GAF=General Assessment of Functioning Scale; HAM-D=Hamilton Scale for Depression; HSRD=Hamilton Rating Scale for Depression; IDS-C=Inventory for Depressive Symptoms(Clinician-Rated); MADRS=Montgomery-Asberg Depression Rating Scale; NOS=not otherwise specified; NR=not reported; PMID=PubMed Identification Number; RCT=randomized controlled trial; ROB=risk of bias; SRS=symptom rating scale; SUM-D=Symptom Subscale for Depression; SUM-ME=Symptom Subscale for Mood Elevation; YMRS = Young Mania Rating Scale
Appendix Table H14Summary risk of bias assessments: lamotrigine for depression
| Drug | Study Funding Source PMID | Overall Risk of Bias Assessment | Rationale |
|---|---|---|---|
| Lamotrigine + mood stabilizers vs. placebo + mood stabilizers | Kemp, 20128 Gov’t+nonprofit 23107222 | Moderate | Randomization and blinding procedures not described. 16% withdrawal. |
Abbreviations: PMID=PubMed Identification Number; YMRS=Young Mania Rating Scale
Appendix Table H15Outcomes summary: lamotrigine for depression
| Drug | Study PMID | Responder/Remitter | Symptom | Function | Other | AE |
|---|---|---|---|---|---|---|
| Lamotrigine + mood stabilizers vs. placebo + mood stabilizers | Kemp, 20128 Gov’t+nonprofit 23107222 | Remission 12 weeks Lamotrigine: 3/23 Placebo: 8/26 NS Response 12 weeks Lamotrigine: 2/23 Placebo: 10/38 p=0.02 Bimodal 12 weeks Lamotrigine: 7/23 Placebo: 8/26 NS | NR | NR | Withdrawal for nonresponse or clinical worsening: Treat:4 Placebo:4 | Severe AE NS Lamotrigine: 1 suicidality, 1 depression hospitalization Placebo: none reported Switching: 2 placebo patients |
Abbreviations: AE=Adverse Events; CGI=Clinical Global Impressions Scale; HAM-D=Hamilton Scale for Depression; MID=minimally important difference; NA=Not applicable; NR=not reported; NS=not significant; PMID=PubMed Identification Number; SAE=Serious Adverse Events; YMRS =Young Mania Rating Scale
Appendix Table H16Strength of evidence assessment: lamotrigine for depression
| Comparison | Outcome | # Studies/Design (n analyzed) | Finding or Summary Statistic | Study Limitations | Consistency | Directness | Precision | Overall Grade/Conclusion |
|---|---|---|---|---|---|---|---|---|
| Lamotrigine + mood stabilizers vs. placebo + mood stabilizers | Remission 12 wks Response 12 wks Bimodal remission/response 12 wks | 1 RCT (n=133) | See table above | Moderate | Unknown | Direct | Imprecise | Insufficient |
Abbreviations: CGI= Clinical Global Impressions; HAM-D=Hamilton Scale for Depression; n=number of subjects; RCT=randomized controlled trial
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. Antidepressants vs. Placebo
Appendix Table H17Characteristics of eligible studies: antidepressants for depression
| 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 | Followup Duration | Outcomes Reported Withdrawal (%) at endpoint |
|---|---|---|---|---|---|---|
| Sachs, 20079 RCT Multisite 1 Continent Government High 17392295 | N = 366 Mean Age 40 Female 57% White 90% BP I 68% BP-II 32% Outpatient | Major Depressive Episode Substance Abuse Other Mental Health Taking Other Meds Labs/Other Conditions | Paroxetine Initiated at 10mg/day increased up to 40mg/day Bupropion Initiated at 150mg/day increased to maximum 375mg.day | Placebo | 26 weeks | SUM-D SUM-ME MADRS YMRS GAF CGI Adverse Events Withdrawal 44% |
Abbreviations: BP=bipolar disorder; C=Comparison; CGI=Clinical Global Impressions Scale; CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; DSM-IV=Diagnostic and Statistical Manual of Mental Disorders, 4th Revision; GAF=General Assessment of Functioning Scale; HAM-D=Hamilton Scale for Depression; HSRD=Hamilton Rating Scale for Depression; IDS-C=Inventory for Depressive Symptoms(Clinician-Rated); MADRS=Montgomery-Asberg Depression Rating Scale; NOS=not otherwise specified; NR=not reported; PMID=PubMed Identification Number; RCT=randomized controlled trial; ROB=risk of bias; SRS=symptom rating scale; SUM-D=Symptom Subscale for Depression; SUM-ME=Symptom Subscale for Mood Elevation; YMRS = Young Mania Rating Scale
Appendix Table H18Summary risk of bias assessments: Antidepressants for depression
| Drug | Study Funding Source PMID | Overall Risk of Bias Assessment | Rationale |
|---|---|---|---|
| Antidepressives vs. placebo | Sachs, 20079 Government 17392295 | High | Participants were switched to open label after a severe response and they remained in the study, psychotherapies were included and not measured as a confounding effect, and they pool results for all mood stabilizers and antidepressants. 44% attrition |
Abbreviations: PMID=PubMed Identification Number; YMRS=Young Mania Rating Scale
Appendix Table H19Outcomes summary: antidepressants for depression
| Drug | Study PMID | Responder/Remitter | Symptom | Function | Other | AE |
|---|---|---|---|---|---|---|
| Antidepressives vs. placebo | Sachs, 20079 Government 17392295 | Durable recovery 26 weeks NS Transient remission 26 weeks NS | NR | NR | Withdrawal due to clinical worsening: Treat: 34.1% Placebo:33.7% Withdrawal w/out reaching clinical outcome: Treat:6.7% Placebo:7% | Severe AE NS Antidepressants: 8 (4.5%) Placebo: 10 (5.3%) Included (antidepressants, placebo): medical hospitalization(8,1), medical illness(0,2), psychiatric hospitalization for depression or suicidal ideation(6,6), or nonbipolar symptoms(2,1), or increased suicidal ideation without hospitalization(0,1) Switching (10.1%, 10.7%) No reported deaths |
Abbreviations: AE=Adverse Events; CGI=Clinical Global Impressions Scale; HAM-D=Hamilton Scale for Depression; MID=minimally important difference; NA=Not applicable; NR=not reported; NS=not significant; PMID=PubMed Identification Number; SAE=Serious Adverse Events; YMRS =Young Mania Rating Scale
Appendix Table H20Strength of evidence assessment: antidepressants for depression
| Comparison | Outcome | # Studies/Design (n analyzed) | Finding or Summary Statistic | Study Limitations | Consistency | Directness | Precision | Overall Grade/Conclusion |
|---|---|---|---|---|---|---|---|---|
| Antidepressives vs. placebo | Durable recovery 26 wks Transient remission 26 wks Discontinuation 26 wks | 1 RCT (n=366) | See table above | High | Unknown | Direct | Imprecise | Insufficient |
Abbreviations: CGI= Clinical Global Impressions; HAM-D=Hamilton Scale for Depression; n=number of subjects; RCT=randomized controlled trial
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. Lithium
Appendix Table H21Characteristics of eligible studies: lithium depression
| 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 | Followup Duration | Outcomes Reported Withdrawal (%) at endpoint |
|---|---|---|---|---|---|---|
| Nierenberg, 201310 RCT Multisite US Government RoB Low 23288387 | N=283 Mean Age 39 Female 56.5% White 75% African American 17% BP I 76% BP II 24% Outpatient | Currently symptomatic (not defined), requiring a change in medication (Mean YMRS 12.5; MADRS 22.5; CGI severity 4.3) Current lithium use Need for hospitalization Other Medical Conditions Pregnancy | Lithium 600 mg/day for first 2 months; thereafter adjusted as clinically needed + Optimized Personalized Treatment | Optimized Personalized Treatment | 6 months | CGI-BP-S Necessary Clinical Adjustments (study-defined – all medication adjustments needed to respond to clinical need) MADRS YMRS CGI-BP-S LIFE-RIFT Remission Withdrawal 16% |
Abbreviations: BP=bipolar disorder; C=Comparison; CGI=Clinical Global Impressions Scale; CGI-BP=Clinical Global Impressions Scale for Bipolar Disorder; DSM-IV=Diagnostic and Statistical Manual of Mental Disorders, 4th Revision; GAF=General Assessment of Functioning Scale; HAM-D=Hamilton Scale for Depression; HSRD=Hamilton Rating Scale for Depression; IDS-C=Inventory for Depressive Symptoms(Clinician-Rated); MADRS=Montgomery-Asberg Depression Rating Scale; NOS=not otherwise specified; NR=not reported; PMID=PubMed Identification Number; RCT=randomized controlled trial; ROB=risk of bias; SRS=symptom rating scale; SUM-D=Symptom Subscale for Depression; SUM-ME=Symptom Subscale for Mood Elevation; YMRS = Young Mania Rating Scale
Appendix Table H22Summary risk of bias assessments: lithium for depression
| Drug | Study Funding Source PMID | Overall Risk of Bias Assessment | Rationale |
|---|---|---|---|
| Lithium | Nierenberg, 201310 Government 23288387 | Low | Open-label but rater blinded. |
Abbreviations: PMID=PubMed Identification Number; YMRS=Young Mania Rating Scale
Appendix Table H23Outcomes summary: lithium for depression
| Drug | Study PMID | Responder/Remitter | Symptom | Function | Other | AE |
|---|---|---|---|---|---|---|
| Lithium + Optimalized Personalized Treatment (OPT) vs. OPT | Nierenberg, 201310 Low 23288387 | Remission 6 months NS | Necessary Clinical Adjustment 6 months NS Lithium+OPT 1.01 OPT 0.99 YMRS 6 months NS Lithium+OPT −6.35 OPT −5.79 MADRS 6 months NS Lithium+OPT −8.20 OPT −8.84 | CGI-BP-S 6 months NS Lithium+OPT −1.2 OPT −1.5 | Overall Withdrawal Lithium+OPT 17.7% OPT 14.8% | SAE Reported no difference between groups No deaths Suicidal Ideation No difference between groups |
Abbreviations: AE=Adverse Events; CGI=Clinical Global Impressions Scale; HAM-D=Hamilton Scale for Depression; MID=minimally important difference; NA=Not applicable; NR=not reported; NS=not significant; PMID=PubMed Identification Number; SAE=Serious Adverse Events; YMRS =Young Mania Rating Scale
Appendix Table H24Strength of evidence assessment: lithium for depression
| Comparison | Outcome | # Studies/Design (n analyzed) | Finding or Summary Statistic | Study Limitations | Consistency | Directness | Precision | Overall Grade/Conclusion |
|---|---|---|---|---|---|---|---|---|
| Lithium + OPT vs. OPT alone | CGI Clinical Need MADRS YMRS Remission | 1 RCT (n=283) | See table above | Low | Unknown | Direct | Imprecise | Insufficient |
Abbreviations: CGI= Clinical Global Impressions; HAM-D=Hamilton Scale for Depression; n=number of subjects; RCT=randomized controlled trial
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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