Combination Interventions

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

Appendix OCombination Interventions

Publication Details

Appendix Table O1

Characteristics of eligible studies: combination interventions vs. inactive comparators.

Appendix Table O2

Summary risk of bias assessments: combination interventions vs. inactive comparators.

Appendix Table O3

Outcomes summary: combination interventions vs. inactive comparators.

Appendix Table O4

Summary of strength of evidence: combination intervention vs. inactive comparators.

Appendix Table O5

Characteristics of eligible studies: combination interventions vs. active comparators.

Appendix Table O6

Summary risk of bias assessments: combination interventions vs. active comparators.

Appendix Table O7

Outcomes Summary: combination interventions vs. active comparators.

Appendix Table O8

Summary of strength of evidence: combination intervention vs. active comparators.

References for Appendix O

1.: Gonzalez Isasi A, Echeburua E, Liminana JM, et al Psychoeducation and cognitive-behavioral therapy for patients with refractory bipolar disorder: A 5-year controlled clinical trial. European Psychiatry. Dec. 2014 March 2014(Pagination)PMID 23276524. [PubMed: 23276524]

2.: Gonzalez-Isasi A, Echeburua E, Mosquera F, et al Long-term efficacy of a psychological intervention program for patients with refractory bipolar disorder: a pilot study. Psychiatry Research. 2010 Apr 30;176(2–3):161–5. PMID 20096466. [PubMed: 20096466]

3.: Todd NJ, Jones SH, Hart A, et al A web-based self-management intervention for Bipolar Disorder ‘living with bipolar’: a feasibility randomised controlled trial. J Affect Disord. 2014 Dec;169:21–9. PMID 25129531. [PubMed: 25129531]

4.: Miklowitz DJ, George EL, Richards JA, et al A randomized study of family-focused psychoeducation and pharmacotherapy in the outpatient management of bipolar disorder. Archives of General Psychiatry. 2003 Sep;60(9):904–12. PMID 12963672. [PubMed: 12963672]

5.: Fagiolini A, Frank E, Axelson DA, et al Enhancing outcomes in patients with bipolar disorder: results from the Bipolar Disorder Center for Pennsylvanians Study. Bipolar Disorders. 2009 Jun;11(4):382–90. PMID 19500091. [PMC free article: PMC3361715] [PubMed: 19500091]

6.: Zaretsky A, Lancee W, Miller C, et al Is cognitive-behavioural therapy more effective than psychoeducation in bipolar disorder? Canadian Journal of Psychiatry - Revue Canadienne de Psychiatrie. 2008 Jul;53(7):441–8. PMID 18674402. [PubMed: 18674402]

Publication Details

Copyright

Publisher

Agency for Healthcare Research and Quality (US), Rockville (MD)

NLM Citation

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

Appendix Table O1Characteristics of eligible studies: combination interventions vs. inactive comparators

Study, Year Design Location Funder Risk of Bias PMID	Randomized (N) Age (mean) Sex (% Female) Race (% White) Diagnosis (% BP I, II, NOS) Setting	Inclusions Key Exclusions	Intervention Description	Comparison Description	Followup Duration	Outcomes Reported Withdrawal (%) at endpoint
Gonzalez-Isasi, 2014¹ Gonzalez-Isasi, 2010² RCT Spain Non-Government Low 20444503 23276524	N=40 Mean Age 41 (18-63) Female 48% White NR BP NR Outpatient	Euthymic or Subsyndromal; BP I or II (DSM-IV) for at least 2 years, history of severe or unfavorable progression of disease, euthymic or subsyndromal symptoms (BDI>7; YMRS> 6), not receiving any psychotherapy Labs/Other Conditions	Group psychoeducation and CBT consisting of sessions about their disorder, the relationship between thoughts and feelings, anxiety control techniques, cognitive re-structuring, problem-solving and self-esteem, and social skills. -20 weekly sessions, 90 minutes each	Standard pharmacologic treatment (mood stabilizers, antipsychotics, and/or benzodiapines) adjusted by psychiatrist	5 years	BDI YMRS Hospitalizations Withdrawal 5%
Todd, 2014³ RCT UK Government and Non-Government Moderate 25129531	N=122 Age 43 (21-65) Female 72% White 89% BP I 70% BP II 25% Rapid Cycling 5% Outpatient	No current clinical state excluded: Self-reported BP I or II and scoring above a threshold for BP I or II on the MDQ None	Interactive, online recovery informed self-management intervention (Living with Bipolar) based on both psychoeducation and CBT. Ten interactive modules to help subjects learn more about bipolar experiences, increase self-esteem and self-efficacy for managing bipolar, increase ability to self-manage, and develop interpersonal skills. Modules included case studies and mood checking tools. -Access to program for 6 months	Wait list control receiving treatment as usual (general practitioner and/or specialist mental health services).	6 months	ISS Depression QoL.BD-Brief WHO-QOL-bref SASS Withdrawal 25%
Miklowitz 2003⁴ Cohort US Government and Non-Government High 12963672	N=100 Age 36 (18-55) Female 60% White 89% BP NR Outpatient	No current clinical state excluded; BP I or II (DSM-IV) with a hypo/manic, depressed, or mixed episode within the last 3 months, willingness to be on maintained drug regimen, living with or in regular contact with close relatives Substance Abuse; Neurological Disorders	Individual IPSRT and family (or partner) therapy. Individual IPSRT consisted of identifying interpersonal problems, using Social Rhythm Metric form, managing symptoms and identifying triggers, and relapse prevention. Family therapy involved education about BP, identification of triggers, communication enhancement, and problem-solving. -25 sessions of individual therapy and 25 sessions of family-focused therapy (frequency adapted to patient needs)	Treatment as usual: Crisis management (not described, comparison group from previous clinical trial)	12 months	Relapse SADS-C Depression SADS-C Mania Time to Recurrence Withdrawal 28%

: Abbreviations: BDI=Beck depression inventory; BP=bipolar disorder; DSM-IV= Diagnostic and statistical manual, 4^th edition; ISS=Internal States Scale; MDQ=Mood Disorder Questionnaire; NOS=not otherwise specified; NR=not reported; PMID=PubMed Identification Number; QoL.BD-Brief=Quality of Life,Bipolar Disorder; RCT=randomized controlled trial; SADS-C= Schedule for Affective Disorders and Schizophrenia, change version; SASS=Simpson Angus Scale score; WHO-QOL-bref=World Health Organization Quality of Life –short version; YMRS = Young Mania Rating Scale

Appendix Table O2Summary risk of bias assessments: combination interventions vs. inactive comparators

Study Funder PMID	Overall Risk of Bias Assessment	Rationale
Gonzalez-Isasi, 2014¹ Gonzalez-Isasi, 2010² Non-Government 20444503 23276524	Low	No significant suspected biases.
Todd, 2014³ Government and Non-Government 25129531	Moderate	Suspected bias due to process for selection. Participant eligibility was based self-reported diagnosis and online clinical questioonare.
Miklowitz 2003⁴ Government and Non-Government 12963672	High	Suspected bias due to process for selection. Partcipants were not randomized to treatment or comparator arm. Data used for comparison was from a previous study.

: Abbreviations: PMID=PubMed Identification Number

Appendix Table O3Outcomes summary: combination interventions vs. inactive comparators

Study PMID	Responder/Remitter	Symptom	Function	Other	AE
Gonzalez-Isasi 2010² 20444503 Gonzalez-Isasi 2014¹ 23276524	NR	Depression* 11 months, BDI Favors combination intervention ES=−0.83 (95% CI −1.47, −0.18) 17 months, BDI Favors combination intervention ES=−1.21 (95% CI −1.89, −0.53) 5 years, BDI Favors combination intervention ES=−2.17 (95% CI −2.95, −1.37) Mania* 11 months, YMRS Favors combination intervention ES=−1.0 (95% CI −1.60, −0.30) 17 months, YMRS Favors combination intervention ES=−1.5 (95% CI −2.2, −0.80) 5 years, YMRS Favors combination intervention ES=−1.10 (95% CI −1.80, −0.40)	NR	Hospitalizations Significant difference between groups at 17-months (p=0.015). No difference at 11-months (p=0.12) or 5-years (p=0.11).	NR
Todd 2014³ 25129531	NR	Depression* 6 months, ISS Depression Favors combination intervention ES=−0.44 (95% CI −0.83, −0.05)	Quality of Life* 6 months, QoL.BD-Brief Favors combination intervention ES=0.42 (95% CI 0.04, 0.82) Social Function* 6 months, SASS Favors combination intervention ES=0.54 (95% CI 0.14, 0.93)	NR	NR
Miklowitz 2003⁴ 12963672	Relapse* 12 months, Any Type NS OR=0.68 (95% CI 0.24, 1.85); p=0.50 Time to Recurrence 12 months Favors combination intervention HR=0.078, p<0.02 42.5 (2.2) weeks IFIT vs. 34.5 (2.5) weeks CM	SADS-C Depression 12 months Favors combination intervention, p < 0.0001. SADS-C Mania 12 months NS, p >0.10	NR	NR	NR

: Abbreviations: AE=Adverse Events; BDI=Beck depression inventory; CI=Confidence Interval; CM=Clinical Management; ES=Effect Size; HR=Hazard Ratio; IFIT=Integrated Family and Individual Therapy; ISS=Internal States Scale; NR=not reported; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; QoL.BD-Brief=Quality of Life,Bipolar Disorder; SADS-C=Schedule for Affective Disorders and Schizophrenia-Change version; SASS=Simpson Angus Scale score; YMRS = Young Mania Rating Scale

Appendix Table O4Summary of strength of evidence: combination intervention vs. inactive comparators

Outcome	Timing	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Relapse	12 months	1 Cohort Study (n=100)	No difference between groups at 12 months.	High	Unclear	Direct	Imprecise	Insufficient
Depression	7-12 months 5 years	3 RCTs (n=262)	Favors combination intervention across multiple time periods.	Low	Consistent	Direct	Imprecise	Insufficient
Mania	7-12 months 5 years	2 RCTs (n=140)	Mixed evidence with no clear direction of effect. No pattern across time periods.	Low	Unclear	Direct	Imprecise	Insufficient
Global Function	NR	-	-	-	-	-	-	-
Other Measures of Function	6 months	1 RCT (n=122)	Favors combination intervention at 6 months.	Moderate	Unclear	Direct	Imprecise	Insufficient

: Abbreviations: NR=not reported; RCT=randomized controlled trial

Appendix Table O5Characteristics of eligible studies: combination interventions vs. active comparators

Study, Year Design Location Funder Risk of Bias PMID	Randomized (N) Age (mean) Sex (% Female) Race (% White) Diagnosis (% BP I, II, NOS) Setting	Inclusions Key Exclusions	Intervention Description	Comparison Description	Followup Duration	Outcomes Reported Withdrawal (%) at endpoint
Fagiolini 2009⁵ RCT US Government Moderate 19500091	N=463 Age 41 (12-75) Female 61% White 83% BP I 68% BP II 19% BP NOS 11% Schizophrenia 2% Outpatient	No current clinical state excluded; BP I, II, or NOS or schizoaffective bipolar subtype disorder (DSM-IV for adults, KSADS-PL for adolescents). Substance Abuse; Other Mental Health; Pregnant/Nursing; Labs/Other Conditions	Enhanced clinical intervention and specialized care for bipolar disorder. Enhanced clinical intervention consisted of 10 basic elements plus specific modules for young, elderly, and African American patients. Elements consisted of education (on disorder, medications, sleep) and management (review of symptoms, discussion and management of side effects, discussion of early waning signs). Additional non-specific support provided to both patient and families. -Weekly enhanced clinical sessions for 12 weeks, then every other week for 8 weeks, and then monthly for remaining time or until they achieved recurrence	Specialized care for bipolar disorder consisting of a manualized system of clinical management included assessment of quality of life, standardized assessments of mood, comprehensive medical evaluations, frequent visits with treatment team, pharmacological treatment and tracking and monitoring of visits.	18 months	CGI BP Depression CGI BP Mania GAF QLESQ Withdrawal 30%
Zaretsky 2008⁶ RCT Canada Government and Non-Government High 18674402	N=79 Age 41 (18-60) Female NR White NR BP I 66% BP II 34% Outpatient	Euthymic/Maintenance; BP I or II, not currently in a full episode, taking a standard mood stabilizer regimen with no change in regimen or prescribing physician in month prior to study entry. Substance Abuse; Schizoaffective; Other Mental Health; Neurological Disorders; Labs/Other Conditions	Psychoeducation and CBT. CBT was based on Basco and Rush manual and emphasized collaborative goal setting, cognitive restructuring, problem-solving, and enhancing interpersonal communication. -7 weekly, audiotaped individual sessions of psychoeducation and 13 weekly, audiotaped individual sessions of CBT	Psychoeducation based on the first five chapters of the Basco and Rush CBT manual. -7 weekly, audiotaped individual sessions	6 months	Relapse HDRS Withdrawal 42%

: Abbreviations: BP=bipolar disorder; CBT=Cognitive Behavioral Therapy; CGI=Clinical Global Impressions Scale; DSM-IV= Diagnostic and statistical manual, 4^th edition; GAF=General Assessment of Functioning Scale; HDRS=Hamilton Depression Rating Scale; KSADS-PL=Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version; NOS=not otherwise specified; NR=not reported; PMID=PubMed Identification Number; RCT=randomized controlled trial

Appendix Table O6Summary risk of bias assessments: combination interventions vs. active comparators

Study Funder PMID	Overall Risk of Bias Assessment	Rationale
Fagiolini 2009⁵ Government 19500091	Moderate	Suspected selection bias due to unclear reporting of randomization process.
Zaretsky 2008⁶ Government and Non-Government 18674402	High	Suspected bias selection bias due to unclear reporting of randomization process and suspected bias due to attrition rate of 42%.

: Abbreviations: PMID=PubMed Identification Number

Appendix Table O7Outcomes Summary: combination interventions vs. active comparators

Study PMID	Responder/Remitter	Symptom	Function	Other	AE
Fagiolini 2009⁵ 19500091	NR	Depression 18 months, CGI Depression NS Mania 18 months, CGI Mania NS	Global Function 18 months, GAF NS Quality of Life 18 months, QLESQ Favors combination intervention.	NR	NR
Zaretsky 2008⁶ 18674402	Relapse* 12 months, Any Type NS OR=1.20 (95% CI 0.23, 6.80); p=0.55	HDRS 12 months Favors combination intervention, p=0.055	NR	NR	NR

: Abbreviations: CGI=Clinical global impression scale; CI=Confidence Interval; GAF=General Assessment of Functioning Scale; HDRS=Hamilton Depression Rating Scale; NR=Not Reported; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; Q-LES-Q=Quality of Life Enjoyment and Satisfaction Questionaire

Appendix Table O8Summary of strength of evidence: combination intervention vs. active comparators

Outcome	Timing	# Studies/Design (n analyzed)	Finding or Summary Statistic	Study Limitations	Consistency	Directness	Precision	Overall Grade/Conclusion
Relapse	12 months	1 RCT (n=79)	No difference between groups at 12 months.	High	Unclear	Direct	Imprecise	Insufficient
Depression	12 months 18 months	2 RCTs (n=542)	Mixed evidence with no clear direction of effect. No pattern across time periods.	High	Inconsistent	Direct	Imprecise	Insufficient
Mania	18 months	1 RCT (n=463)	No difference between groups at 18 months.	High	Unclear	Direct	Imprecise	Insufficient
Global Function	18 months	1 RCT (n=463)	No difference between groups at 18 months	Moderate	Unclear	Direct	Imprecise	Insufficient
Other Measures of Function	18 months	1 RCT (n=463)	Favors combination intervention at 18 months.	Moderate	Unclear	Direct	Imprecise	Insufficient

: Abbreviations: RCT=randomized controlled trial