Review Protocols and Questions

National Collaborating Centre for Mental Health (UK)

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National Collaborating Centre for Mental Health (UK). Bipolar Disorder: The NICE Guideline on the Assessment and Management of Bipolar Disorder in Adults, Children and Young People in Primary and Secondary Care. London: The British Psychological Society and The Royal College of Psychiatrists; 2014 Sep. (NICE Clinical Guidelines, No. 185.)

See 2018 Partial Update

April 2018: Footnotes and cautions have been added and amended to link to the MHRA's latest advice and resources on sodium valproate. Sodium valproate must not be used in pregnancy, and only used in girls and women when there is no alternative and a pregnancy prevention plan is in place. This is because of the risk of malformations and developmental abnormalities in the baby. November 2017: Footnotes for some recommendations were updated with current UK marketing authorisations and MHRA advice. Links to other guidelines have also been updated. Some research recommendations have been stood down. See these changes in the short version of the guideline.

April 2018: Footnotes and cautions have been added and amended to link to the MHRA's latest advice and resources on sodium valproate. Sodium valproate must not be used in pregnancy, and only used in girls and women when there is no alternative and a pregnancy prevention plan is in place. This is because of the risk of malformations and developmental abnormalities in the baby. November 2017: Footnotes for some recommendations were updated with current UK marketing authorisations and MHRA advice. Links to other guidelines have also been updated. Some research recommendations have been stood down. See these changes in the short version of the guideline.

Bipolar Disorder: The NICE Guideline on the Assessment and Management of Bipolar Disorder in Adults, Children and Young People in Primary and Secondary Care.

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APPENDIX 7Review Protocols and Questions

Reviews relating to the experience of carers and the physical health of people with serious mental illness were undertaken in conjunction with a NICE guideline being developed at the same time, Psychosis and Schizophrenia in Adults (2014), which includes the full methods and results of those reviews, including the review protocols.

1. Case identification and assessment

Topic	Interventions
Review question(s)	RQ1.1: For adults at risk of or suspected as having bipolar disorder, what identification instruments when compared with a gold standard diagnosis (based on DSM¹ or ICD² criteria) have adequate clinical utility (that is, clinically useful with good sensitivity and specificity) and reliability? RQ1.2: For children (less than 13 years) and young people (13 to 18 years)at risk of or suspected of having bipolar disorder, what identification instruments when compared with a gold standard diagnosis (based on DSM or ICD criteria) have adequate clinical utility (that is, clinically useful with good sensitivity and specificity) and reliability? RQ1.3: For people with possible bipolar disorder, what are the key components of, and the most effective structure for, diagnostic assessment? What amendments, if any, need to be made for (i) particular cultural or minority ethnic groups, (ii) gender, (iii) children and young people, (iv) older adults?
Objectives	For RQ1.1 and RQ1.2: To identify brief screening instruments to assess need for further assessment of people with suspected bipolar disorder and to assess their diagnostic accuracy. For RQ1.3: To identify the key components of a comprehensive assessment.
Criteria for considering studies for the review
Intervention	For case identification (RQ1.1 and RQ1.2): Brief screening questionnaires (< 15 items) identified by the GDG.
Comparator	Gold standard: DSM or ICD diagnosis of bipolar disorder.
Types of participants	Children and young people (aged 18 years and younger) and adults with suspected bipolar disorder.
Outcomes	Sensitivity (percentage of true cases identified). Specificity (percentage of non-cases excluded).
Study design	Studies had to include participants with and without bipolar disorder completing a case-identification instrument and a diagnostic interview.
Search strategy	Databases searched: Excerpta Medica Database (Embase), MEDLINE, PreMEDLINE, Psychological Information Database (PsycINFO). Date limits: Database inception to 20 January 2014.
Study design filter/limit used	None; no language restriction
Question specific search strategy	Yes
Amendments to search strategy/study design filter	None
Searching other resources
The review strategy	To conduct pooled test accuracy meta-analyses on the sensitivity and specificity of case identification instruments where possible.
Note.

2. Pharmacological and medical interventions for acute episodes

2.1. Pharmacological and nutritional interventions for mania, hypomania, and mixed episodes for adults with bipolar disorder

Topic	Interventions
Review question(s)	RQ2.1: For adults with bipolar disorder, what are the relative benefits and harms of pharmacological and nutritional interventions for mania, hypomania and mixed episodes? What amendments, if any, need to be made for (i) particular cultural or minority ethnic groups, (ii) gender, (iii) adults (18 to 64) and older adults (65+)?
Objectives	To estimate the efficacy of interventions to treat mania, hypomania and mixed episodes.
Criteria for considering studies for the review
Intervention	All licensed oral medications (and their combinations). Nutritional interventions will be analysed separately.
Comparator	Placebo. Other interventions.
Types of participants	Adults (18+) with bipolar disorder who are experiencing an acute episode. Special consideration will be given to the groups above.
Outcomes	1) Response (50% reduction in symptoms). 2) Discontinuation (due to side effects, other).
Time	The main analysis will include outcomes at the end of the acute treatment phase.
Study design	Randomised controlled trials (RCTs) and cluster RCTs with a parallel group design in which providers and participants were blind to treatment. Quasi-RCTs, such as trials in which allocation is determined by alternation or date of birth, and single-blind studies will be excluded.
Dosage	Fixed or flexible doses within the therapeutic range (British National Formulary [BNF] recommended).
Study setting	Primary, secondary, tertiary, health and social care.
Search strategy	Databases searched: RCT: Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, Medical Literature Analysis and Retrieval System Online (MEDLINE), in process bibliographic citations for MEDLINE (PreMEDLINE), PsycINFO. Systematic review (SR): Cochrane Database of Systematic Reviews (CDSR), CINAHL, Cochrane Database of Abstracts of Reviews of Effects (DARE), Embase, MEDLINE, PreMEDLINE, PsycINFO. Date limits: RCT: 2005 to 20 January 2014; SR: 2005 to 11 November 2012.
Study design filter/limit used	RCT; SR. Language restrictions: none.
Question specific search strategy	No
Amendments to search strategy/study design filter	None
Searching other resources	The NCCMH review team will write to all stakeholders, authors of all included studies, and manufacturers of all licensed drugs to request unpublished studies.
The review strategy	The GDG will search for systematic reviews that compare all eligible trials using an appropriate statistical method. If reviews are found, the GDG will assess their quality, completeness and applicability to the NHS. If the GDG identify a systematic review appropriate to the review question, they will search for RCTs conducted or published since the review was conducted, and will assess if any additional trials could affect the conclusions of the previous review. If new trials could change the conclusions, the GDG will update the review and conduct a new analysis. If new trials could not change the conclusions of an existing review, the GDG will use the existing review to inform their recommendations. If no reviews are found, the GDG plans to compare all eligible interventions using pairwise meta-analyses and, if appropriate, conduct a network meta-analysis comparing response and discontinuation at the end of the acute treatment. The GDG will conduct pairwise analyses using random effects models of interventions that are not connected to the main network, including studies with no connected intervention or control group and studies of specific subpopulations (for example, people with comorbid substance abuse). For each study, the following will be extracted: year of study; country; total number of study participants in each included group; inclusion and exclusion criteria; age (mean); gender (percentage female); race (percentage black and minority ethnic [BME]); diagnosis (percentage bipolar I disorder); risk of bias. For each intervention or comparison group of interest, dose, frequency and duration will also be extracted.
Note.

2.2. Pharmacological and nutritional interventions for episodes of acute bipolar depression in adults

Topic	Interventions
Review question(s)	RQ2.2: For adults with bipolar disorder, what are the relative benefits and harms of pharmacological and nutritional interventions for acute episodes of acute bipolar depression? What amendments, if any, need to be made for (i) particular cultural or minority ethnic groups, (ii) gender, (iii) adults (18 to 64) and older adults (65+)?
Objectives	To estimate the efficacy of interventions to treat acute episodes of bipolar depression.
Criteria for considering studies for the review
Intervention	All licensed oral medications (and their combinations). Nutritional interventions will be analysed separately.
Comparator	Placebo Other interventions
Types of participants	Adults (18+) with bipolar disorder who are experiencing an acute episodes of bipolar depression. Special consideration will be given to the groups above.
Outcomes	1) Response (50% reduction in symptoms). 2) Discontinuation (due to side effects, other).
Time	The main analysis will include outcomes at the end of the acute treatment phase.
Study design	Randomised controlled trials (RCTs) and cluster RCTs with a parallel group design in which providers and participants were blind to treatment. Quasi-RCTs, such as trials in which allocation is determined by alternation or date of birth, and single-blind studies, will be excluded.
Dosage	Fixed or flexible doses within the therapeutic range (BNF recommended).
Minimum sample size	To be included in a network meta-analysis, drugs must have been evaluated in at least 20 participants.
Study setting	Primary, secondary, tertiary, health and social care.
Search strategy	Databases searched: RCT: CENTRAL, CINAHL, Embase, MEDLINE, PreMEDLINE, PsycINFO. SR: CDSR, CINAHL, DARE, Embase, MEDLINE, PreMEDLINE, PsycINFO. Date limits: RCT: 2005 to 20 January 2014; SR: 2005 to 11 November 2012.
Study design filter/limit used	RCT; SR. Language restrictions: none.
Question specific search strategy	No
Amendments to search strategy/study design filter	None
Searching other resources	The NCCMH review team will write to all stakeholders, authors of all included studies, and manufacturers of all licensed drugs to request unpublished studies.
The review strategy	The GDG will search for systematic reviews that compare all eligible trials using an appropriate statistical method. If reviews are found, the GDG will assess their quality, completeness and applicability to the NHS. If they identify a systematic review appropriate to the review question, they will search for RCTs conducted or published since the review was conducted, and the GDG will assess if any additional trials could affect the conclusions of the previous review. If new trials could change the conclusions, the GDG will update the review and conduct a new analysis. If new trials could not change the conclusions of an existing review, the GDG will use the existing review to inform their recommendations. If no reviews are found, the GDG plans to compare all eligible interventions using pairwise meta-analyses and, if appropriate, conduct a network meta-analysis comparing response, symptoms of depression and discontinuation at the end of the acute treatment. The GDG will conduct pairwise analyses using random effects models of interventions that are not connected to the main network, including studies with no connected intervention or control group and studies of specific subpopulations (for example, people with comorbid substance abuse). For each study, the following will be extracted: year of study; country; total number of study participants in each included group; inclusion and exclusion criteria; age (mean); gender (percentage female); race (percentage BME); diagnosis (percentage bipolar I disorder); and risk of bias. For each intervention or comparison group of interest, dose, frequency and duration will also be extracted.
Note.

2.3. Non-pharmacological interventions for adults with bipolar disorder

Topic	Interventions
Review question(s)	RQ2.3: For adults with bipolar disorder, what are the relative benefits and harms of acupuncture, bright light therapy, transcranial magnetic stimulation (TMS), and vagus nerve stimulation for mania, hypomania, and mixed episodes? RQ2.4: For adults with bipolar disorder, what are the relative benefits and harms of acupuncture, bright light therapy, transcranial magnetic stimulation (TMS), and vagus nerve stimulation for depressive episodes? What amendments, if any, need to be made for (i) particular cultural or minority ethnic groups, (ii) gender, (iii) adults (18 to 64) and older adults (65+)?
Objectives	To estimate the efficacy of physical interventions for adults with bipolar disorder.
Criteria for considering studies for the review
Intervention	Non-pharmacological medical interventions
Comparator	A credible no-intervention control (for example, sham intervention).
Types of participants	Adults (18+) with bipolar disorder who are experiencing an acute episode. Special consideration will be given to the groups above.
Outcomes	1) Change in symptoms (of mania or depression) 2) Response (50% reduction or greater) 3) Discontinuation
Time	The main analysis will include outcomes at the end of the acute treatment phase.
Study design	Randomised controlled trials (RCTs) and cluster RCTs with a parallel group design. Quasi-RCTs, such as trials in which allocation is determined by alternation or date of birth, will be excluded.
Study setting	Primary, secondary, tertiary, health and social care.
Comparator	A credible no-intervention control (for example, sham intervention).
Types of participants	Adults (18+) with bipolar disorder who are experiencing an acute episode. Special consideration will be given to the groups above.
Outcomes	4) Change in symptoms (of mania or depression). 5) Response (50% reduction or greater). 6) Discontinuation.
Time	The main analysis will include outcomes at the end of the acute treatment phase.
Study design	Randomised controlled trials (RCTs) and cluster RCTs with a parallel group design. We will exclude quasi-RCTs, such as trials in which allocation is determined by alternation or date of birth.
Study setting	Primary, secondary, tertiary, health and social care.
Search strategy	Databases searched: RCT: CENTRAL, CINAHL, Embase, MEDLINE, PreMEDLINE, PsycINFO. SR: CDSR, CINAHL, DARE, Embase, MEDLINE, PreMEDLINE, PsycINFO. Date limits: RCT: 2005 to 20 January 2014; SR: 2005 to 11 November 2012.
Study design filter/limit used	RCT; SR. Language restrictions: none.
Question specific search strategy	No
Amendments to search strategy/study design filter	None
Searching other resources	The NCCMH review team will write to all stakeholders and authors of all included studies to request unpublished studies.
The review strategy	The GDG will conduct pairwise analyses for all comparisons and outcomes using random effects models. For each study, the GDG will also extract: year of study; country; total number of study participants in each included group; inclusion and exclusion criteria; age (mean); gender (percentage female); race (percentage BME); diagnosis (percentage bipolar I); risk of bias. For each intervention or comparison group of interest, dose, frequency and duration will also be extracted.
Note.

3. Long-term management of bipolar disorder

3.1. Service-level intervention for bipolar disorder

Topic	Interventions
Review question(s)	RQ3.1: For adults with bipolar disorder, what are the relative benefits and harms of service-level interventions that are designed specifically for people bipolar disorder? What amendments, if any, need to be made for (i) particular cultural or minority ethnic groups, (ii) gender, and (iii) adults (18 to 64) and older adults (65+)?
Objectives	To estimate the efficacy of services in treating bipolar disorder.
Criteria for considering studies for the review
Intervention	Lithium clinics Mood clinics Collaborative care
Comparator	Treatment-as-usual Other services
Types of participants	Adults (18+) with suspected bipolar disorder. Special consideration will be given to the groups above.
Outcomes	1) Relapse (all, mania/mixed, depression) 2) Hospitalisation (rate, duration) 3) Quality of life 4) Mortality
Time	At least 1 year after initiating treatment.
Study design	Randomised controlled trials (RCTs) and cluster RCTs with a parallel group design. We will exclude quasi-RCTs, such as trials in which allocation is determined by alternation or date of birth.
Search strategy	Databases searched: RCT: CENTRAL, CINAHL, Embase, MEDLINE, PreMEDLINE, PsycINFO. SR: CDSR, CINAHL, DARE, Embase, MEDLINE, PreMEDLINE, PsycINFO Date limits: RCT: 2005 to 20 January 2014; SR: 2005 to 11 November 2012.
Study design filter/limit used	RCT; SR. Language restrictions: none.
Question specific search strategy	No
Amendments to search strategy/study design filter	None
Searching other resources	The NCCMH review team will write to all stakeholders and authors of all included studies to request unpublished studies.
The review strategy	We will conduct pairwise analyses for all comparisons and outcomes using random effects models. For each study, the GDG will also extract: year of study; country; total number of study participants in each included group; inclusion and exclusion criteria; age (mean); gender (percentage female); race (percentage BME); diagnosis (percentage bipolar I); number of previous episodes; risk of bias.
Note.

3.2. Communication technologies for monitoring the symptoms of bipolar disorder

Topic	Interventions
Review question(s)	RQ3.3: What are the relative benefits and harms of information and communication technologies (for example, text messaging) for monitoring symptoms? What amendments, if any, need to be made for (i) particular cultural or minority ethnic groups, (ii) gender, and (iii) adults (18 to 64) and older adults (65+)?
Objectives	To estimate the efficacy of communication technologies for monitoring symptoms.
Criteria for considering studies for the review
Intervention	Internet and computer programmes, automated telephone systems, and text messaging.
Comparator	Waitlist, no-intervention and other interventions.
Types of participants	People with bipolar disorder. Special consideration will be given to the groups above.
Outcomes	1) Relapse (all, mania/mixed, depression). 2) Hospitalisation (rate, duration). 3) Mortality (all-cause, suicide attempts, suicides completed).
Time	Outcomes will be grouped by time point.
Study design	Randomised controlled trials (RCTs) and cluster RCTs with a parallel group design. We will exclude quasi-RCTs, such as trials in which allocation is determined by alternation or date of birth.
Study setting	Primary, secondary, tertiary, health and social care.
Search strategy	Databases searched: RCT: CENTRAL, CINAHL, Embase, MEDLINE, PreMEDLINE, PsycINFO. SR: CDSR, CINAHL, DARE, Embase, MEDLINE, PreMEDLINE, PsycINFO. Date limits: RCT: 2005 to 20 January 2014. SR: 2005 to 11 November 2012.
Study design filter/limit used	RCT; SR. Language restrictions: none.
Question specific search strategy	No
Amendments to search strategy/study design filter	None
Searching other resources	The NCCMH review will team write to all stakeholders and authors of all included studies to request unpublished studies.
The review strategy	The GDG will conduct pairwise analyses for all comparisons and outcomes using random effects models. For each study, the GDG will also extract: year of study; country; total number of study participants in each included group; inclusion and exclusion criteria; age (mean); gender (percentage female); race (percentage BME); diagnosis (percentage bipolar I); number of previous episodes; risk of bias.
Note.

3.3. Pharmacological and nutritional interventions for long-term management of adults with bipolar disorder

Topic	Interventions
Review question(s)	RQ3.4: For adults with bipolar disorder, what are the relative benefits and harms of starting a new pharmacological or nutritional intervention outside of an acute episode? RQ3.5: For adults with bipolar disorder, what are the relative benefits and harms of continuing an acute treatment for 1 year or more? What amendments, if any, need to be made for (i) particular cultural or minority ethnic groups, (ii) gender, and (iii) adults (18 to 64) and older adults (65+)?
Objectives	To estimate the efficacy of interventions for the long-term management of bipolar disorder.
Criteria for considering studies for the review
Intervention	All licensed oral medications (and their combinations) delivered for 1 year or more.
Comparator	Pill placebo Other pharmacological interventions
Types of participants	Adults (18+) with bipolar disorder. Special consideration will be given to the groups above.
Outcomes	1) Relapse (all, mania/mixed, depression) (for the purposes of the guideline, relapse was defined as a new episode meeting criteria for MDD or mania) 2) Discontinuation (due to side effects, other) 3) Hospitalisation (rate) 4) Quality of life 5) Mortality (all-cause, suicides completed) 6) Weight
Time	Included studies must have included controlled measures of outcomes at 12 months or later.
Study design	Randomised controlled trials (RCTs) and cluster RCTs with a parallel group design. We will exclude quasi-RCTs, such as trials in which allocation is determined by alternation or date of birth.
Include unpublished data?	Unpublished research may be included.
Restriction by date?	No limit.
Dosage	Fixed or flexible doses within the therapeutic range (BNF recommended).
Minimum sample size	Ten participants per group.
Study setting	Primary, secondary, tertiary, health and social care.
Search strategy	Databases searched: RCT: CENTRAL, CINAHL, Embase, MEDLINE, PreMEDLINE, PsycINFO. SR: CDSR, CINAHL, DARE, Embase, MEDLINE, PreMEDLINE, PsycINFO. Date limits: RCT: 2005 to 20 January 2014. SR: 2005 to 11 November 2012.
Study design filter/limit used	RCT; SR. Language restrictions: none.
Question specific search strategy	No
Amendments to search strategy/study design filter	None
Searching other resources	The NCCMH review team will write to all stakeholders, authors of all included studies, and manufacturers of all licensed drugs to request unpublished studies.
The review strategy	The GDG will search for systematic reviews that compare all eligible trials using an appropriate statistical method. If reviews are found, the GDG will assess their quality, completeness, and applicability to the NHS. If the GDG identify a systematic review appropriate to the review question, we will search for RCTs conducted or published since the review was conducted, and the GDG will assess if any additional trials could affect the conclusions of the previous review. If new trials could change the conclusions, the GDG will update the review and conduct a new analysis. If new trials could not change the conclusions of an existing review, the GDG will use the existing review to inform their recommendations. If no reviews are found, we plan to compare all eligible interventions using pairwise meta-analyses and, if appropriate, conduct a network meta-analysis comparing relapse and discontinuation. The GDG will conduct pairwise analyses using random effects models of interventions that are not connected to the main network, including studies with no connected intervention or control group and studies of specific subpopulations (for example, people with comorbid substance abuse). For each study, we will also extract: year of study; country; total number of study participants in each included group; inclusion and exclusion criteria; age (mean); gender (percentage female); race (percentage BME); diagnosis (percentage bipolar I); number of previous episodes; risk of bias. For each intervention or comparison group of interest, dose, frequency and duration will also be extracted.
Note.

4. Psychological and psychosocial interventions for adults with bipolar disorder

Topic	Interventions
Review question(s)	Mania RQ4.1: For adults with bipolar disorder, what are the relative benefits and harms of psychological and psychosocial interventions for mania, hypomania, and mixed episodes? RQ4.2: For adults with bipolar disorder, what are the relative benefits and harms of combined psychological and pharmacological interventions for mania, hypomania, and mixed episodes? Depression RQ4.3: For adults with bipolar disorder, what are the relative benefits and harms of psychological and psychosocial interventions for depression? RQ4.4: For adults with bipolar disorder, what are the relative benefits and harms of combined psychological and pharmacological interventions for depression? Long-term management RQ4.5: For adults with bipolar disorder, what are the relative benefits and harms of psychological and psychosocial interventions for longterm management? RQ4.6: For adults with bipolar disorder, what are the relative benefits and harms of combined psychological and pharmacological interventions for long-term management? What amendments, if any, need to be made for (i) particular cultural or minority ethnic groups, (ii) gender?
Sub-question(s)	Does the effectiveness of treatment vary: For RQ6.4 to RQ6.11: For people taking a mood stabiliser (for example, lithium or valproate) and people not taking a mood stabiliser; For RQ6.12 to RQ6.15: For people whose most-recent episode was depressive and people whose most-recent episode was manic; For people with bipolar I and bipolar II; For adults (18 to 64) and older adults (65+).
Objectives	To estimate the efficacy of interventions to treat depression.
Criteria for considering studies for the review
Intervention	RQ4.1 to RQ4.6: All psychological and psychosocial interventions (for example, cognitive behavioural therapy), all combined psychological with (licensed) pharmacological interventions.
Comparator	Wait-list, placebo, and other interventions.
Types of participants	Adults (18+) with bipolar disorder. Special consideration will be given to the groups above.
Outcomes	FOR PEOPLE IN AN ACUTE EPISODE 1) Change in symptoms of depression 2) Change in symptoms of mania 3) Response (50% reduction or greater) 4) Discontinuation 5) Quality of life 6) Psychosocial functioning. FOR PEOPLE WHO ARE EUTHYMIC AT BASELINE 1) Relapse 2) Discontinuation 3) Hospitalisation 4) Quality of life 5) Psychosocial functioning.
Time	The main analysis will include outcomes at the end of treatment. For interventions the GDG considers recommending based on post-treatment results, additional analyses will be conducted for further follow-up data.
Study design	Randomised controlled trials (RCTs) and cluster RCTs with a parallel group design. We will exclude quasi-RCTs, such as trials in which allocation is determined by alternation or date of birth.
Study setting	Primary, secondary, tertiary, health and social care.
Search strategy	Databases searched: RCT: CENTRAL, CINAHL, Embase, MEDLINE, PreMEDLINE, PsycINFO. SR: CDSR, CINAHL, DARE, Embase, MEDLINE, PreMEDLINE, PsycINFO. Date limits: RCT: 2005 to 20 January 2014; SR: 2005 to 11 November 2012.
Study design filter/limit used	RCT; SR. Language restrictions: none.
Question specific search strategy	No
Amendments to search strategy/study design filter	None
Searching other resources	The NCCMH review team will write to stakeholders and authors of all included studies to request unpublished studies.
The review strategy	The GDG will conduct pairwise analyses for all comparisons and outcomes using random effects models. For each study, the GDG will also extract: year of study; country; total number of study participants in each included group; inclusion and exclusion criteria; age (mean); gender (percentage female); race (percentage BME); diagnosis (percentage bipolar I); number of previous episodes; risk of bias. For each intervention or comparison group of interest, dose, frequency and duration will also be extracted.
Note.

5. Interventions for children and young people with bipolar disorder

5.1. Pharmacological and nutritional interventions for mania, hypomania and mixed episodes of bipolar disorder in children and young people

Topic	Interventions
Review question(s)	RQ5.1: For children and young people with bipolar disorder, what are the relative benefits and harms of pharmacological and nutritional interventions for mania, hypomania and mixed episodes? What amendments, if any, need to be made for (i) particular cultural or minority ethnic groups, (ii) gender, (iii) for children (younger than 13 years) and young people (13 to 18 years).
Objectives	To estimate the efficacy of interventions to treat manic, hypomanic and mixed episodes.
Criteria for considering studies for the review
Intervention	All licensed oral medications (and their combinations). Nutritional interventions (for example, herbal supplements, fatty acid supplementation).
Comparator	Waitlist, no intervention, placebo and other interventions.
Types of participants	Children (younger than 13 years) and young people (13 to 18 years) with bipolar disorder. Special consideration will be given to the groups above.
Outcomes	1) Change in symptoms of mania. 2) Response (50% reduction or greater). 3) Discontinuation (because of side effects, other).
Time	The main analysis will include outcomes at the end of the acute treatment phase.
Study design	Randomised controlled trials (RCTs) and cluster RCTs with a parallel group design in which providers and participants were blind to treatment. Quasi-RCTs, such as trials in which allocation is determined by alternation or date of birth, and single-blind studies, will be excluded.
Dosage	Fixed or flexible doses within the therapeutic range (BNF recommended).
Study setting	Primary, secondary, tertiary health and social care.
Search strategy	Databases searched: RCT: CENTRAL, CINAHL, Embase, MEDLINE, PreMEDLINE, PsycINFO. SR: CDSR, CINAHL, DARE, Embase, MEDLINE, PreMEDLINE, PsycINFO. Date limits: RCT: 2005 to 20 January 2014. SR: 2005 to 11 November 2012.
Study design filter/limit used	RCT: all languages. SR: English language limit.
Question specific search strategy	No
Amendments to search strategy/study design filter	None
Searching other resources	The NCCMH review team will write to all stakeholders and authors of all included studies to request unpublished studies.
The review strategy	The GDG will conduct pairwise analyses for all comparisons and outcomes using random effects models. For each study, the following will be extracted: year of study; country; total number of study participants in each included group; inclusion and exclusion criteria; age (mean); gender (percentage female); race (percentage black and minority ethnic [BME]); diagnosis (percentage bipolar I); risk of bias. For each intervention or comparison group of interest, dose, frequency and duration will also be extracted.
Note.

5.2. Pharmacological and nutritional interventions for episodes of bipolar depression in children and young people

Topic	Interventions
Review question(s)	RQ5.2: For children and young people with bipolar disorder, what are the relative benefits and harms of pharmacological and nutritional interventions for episodes of bipolar depression? What amendments, if any, need to be made for (i) particular cultural or minority ethnic groups, (ii) gender, (iii) for children (younger than 13 years) and young people (13 to 18 years).
Objectives	To estimate the efficacy of interventions to treat episodes of bipolar depression.
Criteria for considering studies for the review
Intervention	All licensed oral medications (and their combinations). Nutritional interventions (for example, herbal supplements, fatty acid supplementation).
Comparator	Waitlist, no intervention, placebo and other interventions.
Types of participants	Children (younger than 13 years) and young people (13 to 18 years) with bipolar disorder. Special consideration will be given to the groups above.
Outcomes	1) Change in symptoms of depression. 2) Response (50% reduction or greater). 3) Discontinuation (due to side effects, other).
Time	The main analysis will include outcomes at the end of the acute treatment phase.
Study design	RCTs and cluster RCTs with a parallel group design in which providers and participants were blind to treatment. Quasi-RCTs, such as trials in which allocation is determined by alternation or date of birth, and single-blind studies, will be excluded.
Dosage	Fixed or flexible doses within the therapeutic range (BNF recommended).
Study setting	Primary, secondary, tertiary health and social care.
Search strategy	Databases searched: RCT: CENTRAL, CINAHL, Embase, MEDLINE, PreMEDLINE, PsycINFO. SR: CDSR, CINAHL, DARE, Embase, MEDLINE, PreMEDLINE, PsycINFO. Date limits: RCT: 2005 to 20 January 2014. SR: 2005 to 11 November 2012.
Study design filter/limit used	RCT: all languages. SR: English language limit.
Question specific search strategy	No
Amendments to search strategy/study design filter	None
Searching other resources	The NCCMH review team will write to all stakeholders and authors of all included studies to request unpublished studies.
The review strategy	The GDG will conduct pairwise analyses for all comparisons and outcomes using random effects models. For each study, the following will be extracted: year of study; country; total number of study participants in each included group; inclusion and exclusion criteria; age (mean); gender (percentage female); race (percentage BME); diagnosis (percentage bipolar I); risk of bias. For each intervention or comparison group of interest, dose, frequency and duration will also be extracted.
Note.

5.3. Pharmacological and nutritional interventions for long-term management of bipolar disorder in children and young people

Topic	Interventions
Review question(s)	RQ5.3: For children and young people with bipolar disorder, what are the relative benefits and harms of pharmacological and nutritional interventions for long-term management? What amendments, if any, need to be made for (i) particular cultural or minority ethnic groups, (ii) gender, (iii) for children (younger than 13 years) and young people (13 to 18 years).
Objectives	To estimate the efficacy of interventions for the long-term management of bipolar disorder.
Criteria for considering studies for the review
Intervention	All licensed oral medications (and their combinations) or nutritional intervention delivered for 1 year or more.
Comparator	Pill placebo. Other pharmacological or nutritional interventions.
Types of participants	Children (younger than 13 years) and young people (13 to 18 years) with bipolar disorder. Special consideration will be given to the groups above.
Outcomes	1) Relapse (all, mania/mixed, depression). 2) Discontinuation (due to side effects, other) 3) Hospitalisation (rate). 4) Quality of life 5) Mortality (all-cause, suicides completed) 6) Weight.
Time	At least 1 year after initiating treatment.
Study design	RCTs and cluster RCTs with a parallel group design. Quasi-RCTs, such as trials in which allocation is determined by alternation or date of birth, will be excluded.
Study setting	Primary, secondary, tertiary health and social care
Search strategy	Databases searched: RCT: CENTRAL, CINAHL, Embase, MEDLINE, PreMEDLINE, PsycINFO. SR: CDSR, CINAHL, DARE, Embase, MEDLINE, PreMEDLINE, PsycINFO. Date limits: RCT: 2005 to 20 January 2014. SR: 2005 to 11 November 2012.
Study design filter/limit used	RCT: all languages. SR: English language limit.
Question specific search strategy	No
Amendments to search strategy/study design filter	None
Searching other resources	The NCCMH review team will write to all stakeholders and authors of all included studies to request unpublished studies.
The review strategy	The GDG will conduct pairwise analyses for all comparisons and outcomes using random effects models. For each study, the following will be extracted: year of study; country; total number of study participants in each included group; inclusion and exclusion criteria; age (mean); gender (percentage female); race (percentage BME); diagnosis (percentage bipolar I); number of previous episodes; risk of bias. For each intervention or comparison group of interest, dose, frequency and duration will also be extracted.
Note.

5.4. Psychological interventions for bipolar disorder in children and young people

Topic	Interventions
Review question(s)	RQ5.4: For children and young people with bipolar disorder, what are the relative benefits and harms of psychological and psychosocial interventions for episodes of bipolar depression? RQ5.5: For children and young people with bipolar disorder, what are the relative benefits and harms of psychological and psychosocial interventions for long-term management? What amendments, if any, need to be made for (i) particular cultural or minority ethnic groups, (ii) gender, (iii) for children (younger than 13 years) and young people (13 to 18 years)?
Objectives	To estimate the efficacy of psychological interventions to manage bipolar disorder in children and young people.
Criteria for considering studies for the review
Intervention	All psychological and psychosocial interventions (for example, cognitive behavioural therapy) with or without pharmacological interventions.
Comparator	Waitlist, no intervention and other interventions.
Types of participants	Children (younger than 13 years) and young people (13 to 18 years) with bipolar disorder. Special consideration will be given to the groups above.
Outcomes	1) Change in symptoms of depression. 2) Response (50% reduction or greater). 3) Relapse (all, mania/mixed, depression). 4) Discontinuation (due to side effects, other).
Time	For treatments, the main analysis will include outcomes at the end of the intervention. For long-term management, the main analysis will include outcomes after at least 1 year.
Study design	RCTs and cluster RCTs with a parallel group design. Quasi-RCTs, such as trials in which allocation is determined by alternation or date of birth, will be excluded.
Study setting	Primary, secondary, tertiary health and social care.
Search strategy	Databases searched: RCT: CENTRAL, CINAHL, Embase, MEDLINE, PreMEDLINE, PsycINFO. SR: CDSR, CINAHL, DARE, Embase, MEDLINE, PreMEDLINE, PsycINFO. Date limits: RCT: 2005 to 20 January 2014. SR: 2005 to 11 November 2012.
Study design filter/limit used	RCT: all languages. SR: English language limit.
Question specific search strategy	No
Amendments to search strategy/study design filter	None
Searching other resources	The NCCMH review team will write to all stakeholders and authors of all included studies to request unpublished studies.
The review strategy	The GDG will conduct pairwise analyses for all comparisons and outcomes using random effects models. For each study, the following will be extracted: year of study; country; total number of study participants in each included group; inclusion and exclusion criteria; age (mean); gender (percentage female); race (percentage BME); diagnosis (percentage bipolar I); number of previous episodes; risk of bias. For each intervention or comparison group of interest, dose, frequency and duration will also be extracted.
Note.

5.5. Service-level intervention for bipolar disorder

Topic	Interventions
Review question(s)	RQ5.6: For children and young people with bipolar disorder, what are the relative benefits and harms of service-level interventions that are designed specifically for people bipolar disorder? What amendments, if any, need to be made for (i) particular cultural or minority ethnic groups, (ii) gender, (iii) for children (younger than 13 years) and young people (13 to 18 years).
Objectives	To estimate the efficacy of services in treating bipolar disorder.
Criteria for considering studies for the review
Intervention	1) Lithium clinics. 2) Mood clinics. 3) Collaborative care.
Comparator	Treatment-as-usual. Other services.
Types of participants	Children and young people (aged 18 years and younger) with suspected bipolar disorder. Special consideration will be given to the groups above.
Outcomes	1) Relapse (all, mania/mixed, depression). 2) Hospitalisation (rate, duration). 3) Quality of life. 4) Mortality.
Time	At least 1 year after initiating treatment.
Study design	Randomised controlled trials (RCTs) and cluster RCTs with a parallel group design. We will exclude quasi-RCTs, such as trials in which allocation is determined by alternation or date of birth.
Search strategy	Databases searched: RCT: CENTRAL, CINAHL, Embase, MEDLINE, PreMEDLINE, PsycINFO. SR: CDSR, CINAHL, DARE, Embase, MEDLINE, PreMEDLINE, PsycINFO. Date limits: RCT: 2005 to 20 January 2014; SR: 2005 to 11 November 2012.
Study design filter/limit used	RCT; SR. Language restrictions: none.
Question specific search strategy	No
Amendments to search strategy/study design filter	None
Searching other resources	The NCCMH review team will write to all stakeholders and authors of all included studies to request unpublished studies.
The review strategy	We will conduct pairwise analyses for all comparisons and outcomes using random effects models. For each study, the GDG will also extract: year of study; country; total number of study participants in each included group; inclusion and exclusion criteria; age (mean); gender (percentage female); race (percentage BME); diagnosis (percentage bipolar I); number of previous episodes; risk of bias.
Note.

Footnotes

1: Diagnostic and Statistical Manual of Mental Disorders.
2: International Classification of Diseases.

All rights reserved. No part of this guideline may be reprinted or reproduced or utilised in any form or by any electronic, mechanical, or other means, now known or hereafter invented, or in any information storage or retrieval system, without permission in writing from the National Collaborating Centre for Mental Health. Enquiries in this regard should be directed to the Centre Administrator: ku.ca.hcyspcr@nimdAHMCCN

Bookshelf ID: NBK545976

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National Collaborating Centre for Mental Health (UK). Bipolar Disorder: The NICE Guideline on the Assessment and Management of Bipolar Disorder in Adults, Children and Young People in Primary and Secondary Care. London: The British Psychological Society and The Royal College of Psychiatrists; 2014 Sep. (NICE Clinical Guidelines, No. 185.) APPENDIX 7, Review Protocols and Questions.
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Case identification and assessment
Pharmacological and medical interventions for acute episodes
Long-term management of bipolar disorder
Psychological and psychosocial interventions for adults with bipolar disorder
Interventions for children and young people with bipolar disorder

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