• Scottish Intercollegiate Guidelines Network (SIGN). Bipolar affective disorder. A national clinical guideline. Edinburgh (Scotland): Scottish Intercollegiate Guidelines Network (SIGN); 2005 May. 41 p. (SIGN publication; no. 82). [182 references]

Bipolar affective disorder

Diagnosis
Treatment

Family Practice
Internal Medicine
Psychiatry
Psychology

Advanced Practice Nurses
Allied Health Personnel
Nurses
Pharmacists
Physician Assistants
Physicians
Psychologists/Non-physician Behavioral Health Clinicians
Substance Use Disorders Treatment Providers

To present evidence-based recommendations for the management of bipolar affective disorder

Adults (aged 18 years or over) with bipolar affective disorder

Diagnosis

1. Assess signs and symptoms of mania and hypomania, depression, psychotic symptoms, and mixed affective states
2. Clinical assessment according to criteria from the International Classification of Diseases of the World Health Organisation, 10th edition (ICD-10) and the Diagnostic and Statistical Manual, 4^th edition (DSM-IV)
3. Clinical Interview for DSM (SCID)
4. Present State Examination (PSE)
5. Diagnostic scales

Treatment

Acute Mania

1. Antipsychotic drugs
2. Valproic acid salts
3. Carbamazepine
4. Other anticonvulsants
5. Lithium alone or in combination with an antipsychotic
6. Benzodiazepines
7. Electroconvulsive treatment (ECT)
8. Reduction or discontinuation of antidepressant drug treatment

Acute Depression

1. Antidepressant drugs in combination with antimanic drug
2. Lamotrigine
3. Electroconvulsive treatment

Rapid Cycling and Mixed Affective States

Note: Guideline developers considered but did not specifically recommend lithium, antipsychotic drugs, anticonvulsant mood stabilizers, or valproate for rapid cycling and mixed affective states

Management

1. Pharmacologic relapse prevention
   • Lithium
   • Carbamazepine
   • Lamotrigine

   Note: Guideline developers considered but did not recommend valproic acid salts, antipsychotic medications, or antidepressant drugs for relapse prevention

2. Psychosocial interventions
3. Reproductive health issues
   • Contraception
   • Preconception counseling
   • Drugs in pregnancy

     Note: Guideline developers considered but did not recommend newer antipsychotic drugs during pregnancy. They discussed but did not offer specific recommendations regarding antidepressant drug use during pregnancy.

   • Drug treatment and lactation

4. Substance misuse
   • Manage under Care Programme Approach (CPA)
5. Suicide prevention
• Optimize acute and maintenance lithium treatment

• Accuracy of diagnostic tools (e.g., sensitivity and specificity of diagnostic scales)
• Effectiveness of treatments on stabilizing mood and preventing relapse
• Morbidity and mortality associated with bipolar affective disorder
• Adverse effects of medication used to treat bipolar disorder

Searches of Electronic Databases

The evidence base for this guideline was synthesised in accordance with Scottish Intercollegiate Guidelines Network (SIGN) methodology. A systematic review of the literature was carried out using an explicit search strategy devised by the SIGN Information Officer in collaboration with members of the guideline development group. Literature searches were initially conducted in Medline, Embase, Cinahl, Psychinfo, and the Cochrane Library using the year range 1990-2003. The literature search was updated with new material during the course of the guideline development process. A final update search was performed in April 2004. Key Web sites on the Internet were also used, such as the National Guidelines Clearinghouse. These searches were supplemented by reference lists of relevant papers and group members' own files. The Medline version of the main strategies can be found on the SIGN Web site. The work of the guideline groups for postnatal depression and puerperal psychosis and diagnosis and management of epilepsy in adults formed the basis of some of the recommendations in section 5 of the original guideline document.

Not stated

Weighting According to a Rating Scheme (Scheme Given)

Levels of Evidence

1++: High quality meta-analyses, systematic reviews of randomised controlled trials (RCTs), or RCTs with a very low risk of bias

1+: Well conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias

1-: Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias

2++: High quality systematic reviews of case control or cohort studies; high quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal

2+: Well conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal

2-: Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal

3: Non-analytic studies (e.g., case reports, case series)

4: Expert opinion

Review of Published Meta-Analyses
Systematic Review with Evidence Tables

Expert Consensus

Note: The grade of recommendation relates to the strength of the evidence on which the recommendation is based. It does not reflect the clinical importance of the recommendation.

Grade A: At least one meta-analysis, systematic review of randomized controlled trials (RCTs), or RCT rated as 1++ and directly applicable to the target population; or

A body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results

Grade B: A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or

Extrapolated evidence from studies rated as 1++ or 1+

Grade C: A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or

Extrapolated evidence from studies rated as 2++

Grade D: Evidence level 3 or 4; or

Extrapolated evidence from studies rated as 2+

Good Practice Points: Recommended best practice based on the clinical experience of the guideline development group

Treatments for Acute Mania

Limited good quality economics studies were found on the relative cost effectiveness of treatments for acute mania. One cost-consequence study from the United States found that over a 12-week period, treatment with semisodium valproate or olanzapine produced similar clinical outcomes but showed no significant differences in total costs of care. A National Institute for Clinical Excellence (NICE) technology appraisal examining the use of olanzapine and semisodium valproate for acute mania concluded that no distinction could be made between the two drugs on cost effectiveness grounds. Two other studies were found relating to acute treatment but the applicability of the findings in each case was limited by poor quality methodology. No cost effectiveness studies were found relating to the treatment of acute bipolar depression in patients with a history of mania.

Pharmacological Treatments for Relapse Prevention

No cost-effectiveness studies were found relating to pharmacological treatments for relapse prevention. No full economic evaluations were found on psychosocial interventions to prevent relapse, but several clinical trials on such interventions did report information on resource use. Two studies concluded that cognitive therapy produced improvements in symptoms and functioning compared to waiting list control patients, in addition to reductions in hospital admissions. Using psychologists to train individuals to recognize early symptoms of relapse has also been shown to be effective in reducing manic relapses (but not depressive relapses) but, contrary to the findings above, this was not associated with significant reductions in inpatient stays, outpatient visits, or community contacts.

External Peer Review
Internal Peer Review

The national open meeting is the main consultative phase of Scottish Intercollegiate Guidelines Network (SIGN) guideline development, at which the guideline development group presents its draft recommendations for the first time. The national open meeting for this guideline was held in November 2003 and was attended by all of the key specialties relevant to the guideline. The draft guideline was also available on the SIGN Web site for one month to allow those unable to attend the meeting to contribute to the development of the guideline.

The guideline was also reviewed in draft form by a panel of independent expert referees, who were asked to comment primarily on the comprehensiveness and accuracy of interpretation of the evidence base supporting the recommendations in the guideline.

As a final quality control check, the guideline was reviewed by an editorial group comprising the relevant specialty representatives on SIGN Council to ensure that the specialist reviewers' comments have been addressed adequately and that any risk of bias in the guideline development process as a whole has been minimised.

Note from the Scottish Intercollegiate Guidelines Network (SIGN) and National Guideline Clearinghouse (NGC): In addition to these evidence-based recommendations, the guideline development group also identifies points of best clinical practice in the full-text guideline document.

The grades of recommendations (A-D) and levels of evidence (1++, 1+, 1-, 2++, 2+, 2-, 3, 4) are defined at the end of the "Major Recommendations" field.

Definitions and Diagnosis

Diagnostic Scales

D - A diagnosis of bipolar affective disorder should be made after clinical assessment according to Diagnostic and Statistical Manual (DSM) or International Classification of Diseases of the World Health Organisation (ICD) criteria

Acute Treatment

Recommendations for the Treatment of Acute Mania

A - Acute manic episodes should be treated with oral administration of an antipsychotic drug or semisodium valproate.

A - Lithium can be used if immediate control of overactive or dangerous behaviour is not needed or otherwise should be used in combination with an antipsychotic.

Recommendations for the Treatment of Acute Depression

B - An antidepressant in combination with an antimanic drug (lithium, semisodium valproate or an antipsychotic drug), or lamotrigine is recommended for the treatment of acute bipolar depression in patients with a history of mania.

Maintenance

Pharmacological Relapse Prevention

Lithium

A - Lithium is the treatment of choice for relapse prevention in bipolar affective illness.

A - Lithium should be prescribed at an appropriate dose with a daily dosing regimen.

A - The withdrawal of lithium should be gradual to minimise the risk of relapse.

Carbamazepine

A - Carbamazepine can be used as an alternative to lithium, particularly in patients with bipolar II, or when lithium is ineffective or unacceptable.

Lamotrigine

A - Lamotrigine can be used for prophylaxis in patients who have initially stabilised with lamotrigine, particularly if depressive relapse is a greater problem than manic relapse.

Recommendations on Psychosocial Interventions

B - Evidence based psychosocial interventions should be available to patients in addition to pharmacological maintenance treatment, especially if complete or continued remission cannot be achieved.

Reproductive Health Issues

Contraception

Combined Oral Contraception (COC)

D - The dose of the combined oral contraceptive should be adjusted accordingly when given with an enzyme-inducing drug

D - Women should be warned that the efficacy of the COC is reduced

D - Barrier methods of contraception should also be used for maximal contraceptive effect

Progesterone-Only Contraception

D - The progestogen-only oral contraceptive is not recommended for women taking enzyme-inducing drugs

D - Depot injections of progesterone may be used with enzyme-inducing drugs if given every 10 weeks

D - Progesterone implants are not suitable for women taking enzyme-inducing drugs

Drugs in Pregnancy

Anticonvulsant Drugs (ACDs)

C - All women on antiepileptic drugs as mood stabilisers should be prescribed a daily dose of 5 mg folic acid from preconception at least until the end of the first trimester.

D - Valproate should be avoided as a mood stabiliser in pregnancy.

Lithium

C - Women with severe bipolar disorder, who are maintained on lithium, can be continued on lithium during pregnancy if clinically indicated.

C - The serum levels of women who are maintained on lithium therapy during pregnancy should be carefully monitored. Detailed fetal ultrasound scanning should be offered.

Benzodiazepines

B - Benzodiazepines should be avoided in the first trimester of pregnancy

Drug Treatment and Lactation

Lithium

D - Mothers taking lithium should be encouraged to avoid breast feeding, particularly if the infant is not full-term and healthy. If a decision is made to proceed, close monitoring of the infant, including serum lithium levels, should be undertaken.

Other Psychotropic Medication

D - New prescriptions for benzodiazepines should be avoided in breastfeeding mothers.

Note: This recommendation does not cover drug dependence, where breast feeding may be beneficial if the infant has been exposed to benzodiazepines in utero.

Suicide Prevention

D - Acute and maintenance lithium treatment of patients with bipolar affective disorders should be optimised to make every effort to minimise the risk of suicide.

Definitions:

Levels of Evidence

1++: High quality meta-analyses, systematic reviews of randomised controlled trials (RCTs), or RCTs with a very low risk of bias

1+: Well conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias

1-: Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias

2++: High quality systematic reviews of case control or cohort studies; high quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal

2+: Well conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal

2-: Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal

3: Non-analytic studies (e.g., case reports, case series)

4: Expert opinion

Grades of Recommendation

Note: The grade of recommendation relates to the strength of the evidence on which the recommendation is based. It does not reflect the clinical importance of the recommendation.

A: At least one meta-analysis, systematic review of RCTs, or RCT rated as 1++ and directly applicable to the target population; or

A body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results

B: A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or

Extrapolated evidence from studies rated as 1++ or 1+

C: A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or

Extrapolated evidence from studies rated as 2++

D: Evidence level 3 or 4; or

Extrapolated evidence from studies rated as 2+

Good Practice Points: Recommended best practice based on the clinical experience of the guideline development group

None provided

The type of supporting evidence is identified and graded for each recommendation (see "Major Recommendations").

Overall Potential Benefits

• Long term prevention of illness is an important treatment aim.
• Interventions may help stabilize mood and prevent relapse.
• Effective diagnosis, treatment, and prevention may improve patients' well-being and productivity and may reduce morbidity and mortality associated with bipolar affective disorder.

Specific Potential Benefits

• Lithium: Three small but well conducted meta-analyses indicate that lithium is effective in reducing early and later relapse in patients with bipolar affective disorder for up to three years.
• Carbamazepine: Carbamazepine may be as effective as lithium in preventing relapse over six weeks to three years, although two studies report superiority of lithium over carbamazepine in patients with bipolar I, and one of these suggests equivalent efficacy for both drugs in patients with bipolar II disorder.

Lithium

• Sudden withdrawal of lithium may lead to a provocation of manic symptoms.
• Side effects include polyuria and polydipsia, hypothyroidism, gastrointestinal disturbance and tremor. Toxicity occurs at 150% of the upper limit of the therapeutic dose range and may develop as a result of reduced kidney function during general physical illness, or through adverse interactions with other medications, such as diuretics and non-steroidal anti-inflammatory drugs.
• Patients may experience reversible changes in their ability to process information during lithium treatment, and this may have relevance to their driving skills.
• Long term treatment with lithium may show faster age related reduction in kidney function, although very few incidences of kidney failure requiring dialysis have been reported.
• Lithium toxicity has been described in a breastfed infant and lithium is known to impair thyroid and renal function in adults.

Antipsychotic Medications

Potential problems are the absence of antidepressant effects and the risk of tardive movement disorders.

Antidepressant Drugs

They have the potential to induce switching to hypomania or mania and long term monotherapy with (especially tricyclic) antidepressants is not advisable.

Reproductive Health Issues

The main risks associated with psychotropic drugs in later pregnancy are neonatal toxicity or withdrawal syndrome following delivery and the possibility of a long term impact on the infant's neurodevelopment. Similar concerns exist for breast feeding and most psychotropic drugs are not licensed for use during pregnancy and lactation.

Anticonvulsant Drugs (ACDs)

Major and minor fetal malformations occur more commonly in infants exposed to the ACDs carbamazepine, valproate, and lamotrigine during pregnancy. The overall risk of major fetal malformation in any pregnancy of approximately 2% is increased two to three-fold in women taking a single ACD. The relative risk is higher with valproate than carbamazepine or lamotrigine.

This guideline is not intended to be construed or to serve as a standard of care. Standards of care are determined on the basis of all clinical data available for an individual case and are subject to change as scientific knowledge and technology advance and patterns of care evolve. Adherence to guideline recommendations will not ensure a successful outcome in every case, nor should they be construed as including all proper methods of care or excluding other acceptable methods of care aimed at the same results. The ultimate judgement must be made by the appropriate healthcare professional(s) responsible for clinical decisions regarding a particular clinical procedure or treatment plan. This judgement should only be arrived at following discussion of the options with the patient, covering the diagnostic and treatment choices available. It is, however, advised that significant departures from the national guideline or any local guidelines derived from it should be fully documented in the patient's case notes at the time the relevant decision is taken.

Implementation of national clinical guidelines is the responsibility of each National Health Service (NHS) Health Board and is an essential part of clinical governance. It is acknowledged that not every guideline can be implemented immediately on publication, but mechanisms should be in place to ensure that the care provided is reviewed against the guideline recommendations and the reasons for any differences assessed and, where appropriate, addressed. These discussions should involve both clinical staff and management. Local arrangements may then be made to implement the national guideline in individual hospitals, units and practices, and to monitor compliance. This may be done by a variety of means including patient-specific reminders, continuing education and training, and clinical audit.

Key points for audit are identified in the original guideline document.

Getting Better
Living with Illness

Effectiveness
Patient-centeredness

• Scottish Intercollegiate Guidelines Network (SIGN). Bipolar affective disorder. A national clinical guideline. Edinburgh (Scotland): Scottish Intercollegiate Guidelines Network (SIGN); 2005 May. 41 p. (SIGN publication; no. 82). [182 references]

Not applicable: The guideline was not adapted from another source.

2005 May

Scottish Intercollegiate Guidelines Network - National Government Agency [Non-U.S.]

Scottish Executive Health Department

Not stated

Guideline Development Group: Professor Klaus Ebmeier (Chair), Professor of Psychiatry, University of Edinburgh; Dr Benjamin Baig (Secretary), Senior House Officer, Royal Edinburgh Hospital; Ms Ailsa Brown, Health Economist, Greater Glasgow Health Board; Dr Jonathan Cavanagh, Senior Lecturer in Psychiatry, Gartnavel Hospital, Glasgow; Dr Stella Clark, Acting Medical Director, Fife Primary Care NHS Trust; Professor Kate Davidson, Director of Glasgow Institute of Psychosocial Interventions, University of Glasgow; Ms Nadine Dougall, Research Fellow, University of Edinburgh; Mrs Karen Fraser, Principal Pharmacist - Mental Health, Ailsa Hospital, Ayr; Dr Kenneth Lawton, General Practitioner, Aberdeen; Ms Fiona Mitchell, Community Psychiatric Nurse, Westbank Clinic, Falkirk; Dr Anne Nightingale, Consultant Psychotherapist, Lansdowne Clinic, Glasgow; Mr Chris O'Sullivan, Lay representative, Edinburgh; Professor Mick Power, Clinical Psychology Course Director, University of Edinburgh; Professor Ian Reid, Professor of Psychiatry, Aberdeen University; Mr Duncan Service, Senior Information Officer, SIGN Executive; Mrs Marion Shawcross, Social Work Officer, The Mental Welfare Commission for Scotland, Edinburgh; Ms Ailsa Stein, Programme Manager, SIGN Executive; Ms Joanne Topalian, Programme Manager, SIGN Executive; Dr Alan Wade, General Practitioner, Glasgow; Mr Laurence Wilson Lay representative, Glasgow

Declarations of interests were made by all members of the guideline development group. Further details are available from the Scottish Intercollegiate Guidelines Network (SIGN) Executive.

None available

This summary was completed by ECRI on July 15, 2005. The information was verified by the guideline developer on July 26, 2005. This summary was updated by ECRI on November 16, 2006, following the FDA advisory on Lamictal (lamotrigine). This summary was updated by ECRI Institute on November 9, 2007, following the U.S. Food and Drug Administration advisory on Antidepressant drugs. This summary was updated by ECRI Institute on January 10, 2008, following the U.S. Food and Drug Administration advisory on Carbamazepine.