clinical guideline/formulary document...determine the choice of drug, as will age, side effects,...

Mersey Care Clinical Guideline/Formulary Document Reviewed: Jan 2017 (updated September 2018)

Bipolar Affective Disorder Next Review: Jan 2019 1 |

Clinical Guideline/Formulary Document Pharmacy Department Medicines Management Services

BIPOLAR AFFECTIVE DISORDER [BPAD]

Introduction

Bipolar Affective Disorder [BPAD] is a chronic, recurrent cyclical mood disorder associated with high levels of suffering, occupational dysfunction, impaired social life and relationships, as well as increased morbidity and mortality.

Bipolar disorder is often co-morbid with a range of other mental disorders (for example, psychosis, substance misuse, anxiety disorders, personality disorders and ADHD) and this has significant implications for both the course of the disorder and its treatment.

The treatment of BPAD is based primarily on psychotropic medication to reduce the severity of symptoms, stabilise mood and prevent relapse. The treatments are determined by the phase of illness and subtype of disorder. Individual variation in response to medication will often determine the choice of drug, as will age, side effects, interactions and associated cautions, child-bearing potential, previous history, medical comorbidities and individual preferences. Clear, written information about bipolar disorder, treatment options, benefits and side effects should be discussed and provided to service users and carers.

Psychological interventions developed specifically for bipolar disorder or high-intensity psychological interventions should be offered.

Monitoring

BPAD is associated with poor physical health and drug treatments can add to this. NICE recommends a physical health check for people with bipolar disorder, performed at least

annually, to include weight or BMI; diet, nutritional status and level of physical activity; cardiovascular status, including pulse and blood pressure; metabolic status, including fasting blood glucose, glycosylated haemoglobin (HbA1c), prolactin, blood lipid profile, liver function. Renal and thyroid function and calcium levels are necessary, for people taking long-term lithium.

People identified as having rapid or excessive weight, gain, hypertension, diabetes, and abnormal lipid levels, obesity (or risk factors) or are physically inactive should be managed in line with the relevant NICE guidance.

The impact of alcohol, tobacco and illicit drugs on physical and mental health and potential drug interactions with medication should be discussed.

Prescribing Advice

Service users and carers (if appropriate) should be provided with suitable information on the likely benefits and side effects of medication and their views on the choice of medication should be considered.

During review of treatment, service users should be specifically questioned about the efficacy of the medication, functioning, concordance and adverse affects. Side effects should be documented in the case notes and reported via the Yellow Card Scheme.

Prescribe a dose that is appropriate for the phase and severity of the illness and consider age and comorbidities. Do not routinely prescribe a dose above the maximum recommended in the British National Formulary [BNF] or Summary of Product Characteristics [SPC]. A review of doses prescribed should be on going.

Be aware of potential interactions of between mood stabilisers, antipsychotics and antidepressants used for bipolar disorder and also with other prescribed medication.



Antipsychotics The antipsychotics haloperidol, olanzapine, quetiapine and risperidone are recommended by

NICE for bipolar disorders. Aripiprazole (for up to 12 weeks) is also an option for moderate to severe manic episodes in young people aged 13 and older with bipolar I disorder. Antipsychotic treatment should not routinely be continued antipsychotic in young people for longer than 12 weeks.

Baseline tests o Weight or BMI, pulse, blood pressure, fasting blood glucose or HbA1c, blood lipid profile

and ECG (for inpatient or if specified by manufacturer or where clinically appropriate) Ongoing monitoring o Side effects, response to treatment o Pulse and blood pressure after each dose change o Weight or BMI weekly for the first 6 weeks, then at 12 weeks o Blood glucose or HbA1c and blood lipid profile at 12 weeks o Responsibility for monitoring may be transferred to primary care after 12 months or when

the patient’s condition is stabilized Do not start regular combined antipsychotic medication, except for short periods (for

example, when changing medication) Discontinue antipsychotics gradually over at least 4 weeks to minimise risk of relapse.

Lithium Pre-treatment tests: o Weight/BMI; U&Es and Cr, eGFR, Calcium, TFTs, FBC, ECG – good practice and (in

those with cardiovascular disease or risk factors). o Exclude pregnancy. o Check interactions.

Ongoing monitoring: o Plasma lithium levels 1 week after starting lithium and 1 week after every dose change,

and weekly until the levels are stable then plasma lithium every 3 months; U&E including calcium, eGFR; TFTs every 6 months; Weight and BMI.

o Monitor for symptoms of neurotoxicity, including paraesthesia, ataxia, tremor and cognitive impairment, which can occur at therapeutic levels of lithium

Narrow therapeutic index: o Aim for lithium level between 0.4 – 1.0mmol/L (elderly 0.4-0.8mmol/L); o Bloods to be taken 12 hours post dose. o Toxicity is more common at levels above 1mmol/L. Signs of lithium toxicity include: CNS

effects including muscle weakness, muscle twitching, drowsiness and coarse tremor and gastrointestinal effects including increasing anorexia, nausea and diarrhoea.

Ongoing verbal and written information: o The National Patient Safety Agency (NPSA) Lithium Therapy pack should be given to

each person commencing lithium. The pack contains a purple patient information booklet, a monitoring booklet to record blood results and an alert card to be carried by the patient. http://www.nrls.npsa.nhs.uk/alerts/?entryid45=65426

Prescribing Lithium: Lithium should be prescribed by drug name AND by brand. Preparations vary widely in bioavailability; changing the preparation requires the same precautions as the initiation of treatment

Interactions with other drugs: o Due to lithium’s relatively narrow therapeutic index, pharmacokinetic interactions with

other drugs can precipitate lithium toxicity. o Non Steroidal Anti inflammatory drugs (NSAIDS) such as diclofenac, ibuprofen,

naproxen, ketoprofen can increase serum levels of lithium by up to 40%.

http://www.nrls.npsa.nhs.uk/alerts/?entryid45=65426



Lithium continued o Angiotensin Converting Enzyme inhibitors (ACE Inhibitors) such as captopril, enalapril

and ramipril can cause up to a four-fold increase in lithium levels over several weeks o Thiazide diuretics such as bendroflumethiazide can cause an up to four -fold increase in

lithium levels. This is usually apparent in the first 10 days of treatment. o See SPC or BNF for further information on interactions.

Stopping lithium: o If lithium is to be discontinued, the dose should be reduced gradually over a period of at

least four weeks (preferably up to 3 months). Individuals should be warned of the risk of relapse if discontinued abruptly.

Valproate Pre- treatment tests: Baseline FBC, LFTs, weight and BMI Ongoing monitoring: Weight/BMI, FBC and LFTs should be repeated after 6 months then

annually. Albumin and clotting time should be checked if changes in LFTs; check interactions; Monitor for signs and symptoms of blood dyscrasias and liver disorders, sedation, tremor and gait disturbances.

Stopping valproate: Reduce dose gradually over at least 4 weeks to reduce relapse. Teratogenicity: Valproate is a major human teratogen. Medicines containing valproate taken

in pregnancy can cause malformations in approximately 10% of babies and developmental disorders in around 30–40% of children after birth. Valproate is contraindicated in pregnancy and must not be prescribed in pregnancy. In addition, valproate must no longer be prescribed to women or girls of childbearing potential unless the terms of the pregnancy prevention programme (PPP) are met and only if other treatments are ineffective or not tolerated, as judged by an experienced specialist. Women or girls or childbearing potential prescribed valproate should have a Risk Acknowledgement Form completed and signed at least annually. See MHRA Drug Safety Update. The Valproate Pregnancy Prevention Programme is supported by a Patient Guide, a Guide for Healthcare Professionals, annual Risk Acknowledgement Form and Patient Card. See MHRA guidance.

Be aware of potential interactions between valproate and other mood stabilisers particularly carbamazepine and lamotrigine, olanzapine and fluoxetine.

Carbamazepine Pre-treatment tests: U&Es, FBC, LFTs. Baseline measure of weight desirable Monitoring: Weight, FBC, platelets, LFTs baseline and periodically, U&E/Creatinine. Usually

every 6 months. Interactions with other drugs: o Carbamazepine is a potent inducer of hepatic cytochrome P450 and is metabolized by

CYP3A4. Plasma levels of most antidepressants, antipsychotics, benzodiazepines, methadone, theophylline and oestrogens can be reduced by carbamazepine resulting in treatment failure.

o The dose of the combined oral contraceptive should be adjusted accordingly when prescribing an enzyme - inducing drug such as carbamazepine. The efficacy of the contraceptive pill is reduced. Advise that barrier methods of contraception should also be used for maximal contraceptive effect.

o Drugs that inhibit CYP3A4 such as diltiazem, erythromycin, cimetidine and some SSRI’s will increase carbamazepine plasma levels and may lead to toxicity.

Teratogenicity – neural tube defects, craniofacial abnormalities Stopping carbamazepine: Reduce dose slowly over at least one month. Risk of serious skin rashes with carbamazepine is greater in people of Thai or Han Chinese,

Japanese or European descent.

Valproate%20should%20not%20be%20prescribed%20in%20pregnant%20women.%20In%20addition,%20valproate%20medicines%20must%20no%20longer%20be%20used%20in%20women%20or%20girls%20of%20childbearing%20potential%20unless%20a%20Pregnancy%20Prevention%20Programme%20is%20in%20place.

2018_05_17_FINAL_4.0a_Sodium_Valproate_Annual_Risk_Acknowledgement_Form.docx

https://www.gov.uk/drug-safety-update/valproate-medicines-epilim-depakote-contraindicated-in-women-and-girls-of-childbearing-potential-unless-conditions-of-pregnancy-prevention-programme-are-met

https://www.gov.uk/guidance/valproate-use-by-women-and-girls



Lamotrigine Pre-treatment tests: FBC, U&Es, LFTs Monitoring: Serious skin rashes; Follow recommended dose titration in BNF or SPC.

Dosage recommendations are complex, particularly when lamotrigine is used with other anticonvulsant drugs. Interactions with other drugs Lamotrigine can interact with valproate and fluoxetine Lamotrigine is a known human teratogen.

Stopping lamotrigine: Reduce dose slowly over at least 4 weeks to reduce relapse.

Other Topiramate and gabapentin should not be used (off-label) to treat bipolar disorders.

Pharmacological Treatment of Bipolar Disorder - Principles of Management

Bipolar Mania or Hypomania People who develop mania or hypomania and are not currently prescribed an antipsychotic or

mood stabiliser should be offered haloperidol, olanzapine, quetiapine or risperidone, depending on preference, advanced statements, comorbidity, previous response and side effects.

If the first antipsychotic is poorly tolerated or ineffective at the maximum licensed dose, an alternative antipsychotic from the drugs listed above should be offered.

If an alternative antipsychotic is not sufficiently effective at the optimal dose, consider adding lithium. If adding lithium is ineffective, or if lithium is not suitable, consider adding valproate instead. Valproate must not be prescribed in pregnancy. In addition, valproate medicines must no longer be used in women or girls of childbearing potential unless a Pregnancy Prevention Programme is in place. Women or girls or childbearing potential prescribed valproate should have a Risk Acknowledgement Form completed and signed at least annually.

If a person is already prescribed an antidepressant, consider withdrawing the antidepressant at onset of manic or hypomanic episode, abruptly or gradually, as appropriate and initiate an oral antipsychotic, as above.

Short term use of benzodiazepines may be considered to manage severe agitation. People presenting with a mixed affective states should be managed as above and monitored for

the emergence of depression If monotherapy proves ineffective, consider using a combination of an antipsychotic with mood

stabiliser(s). Carbamazepine should not be used routinely, but is licensed for people who are intolerant of

lithium or for whom lithium is ineffective Lamotrigine is not recommended for treatment of manic episodes.

Acute manic or hypomanic episode while already taking antimanic medication For people already taking lithium who develop a manic or hypomanic episode, the plasma

lithium level should be checked and the dose optimised. Adding haloperidol, olanzapine, quetiapine or risperidone to lithium should be considered, depending on the person’s preference and previous response to treatment.

For people already taking valproate or another mood stabiliser, consider increasing the dose, up to the maximum BNF dose, depending on clinical response and side effects. If there is no improvement, consider adding an antipsychotic, as above.

If a service user already taking an antipsychotic experiences a manic episode, the dose should be checked and increased if necessary. An alternative antipsychotic may be tried. If there is no improvement, lithium or valproate should be added.

Valproate must not be prescribed in pregnancy. In addition, valproate medicines must no longer be used in women or girls of childbearing potential unless a Pregnancy Prevention Programme is in place. Women or girls or childbearing potential prescribed valproate should have a Risk Acknowledgement Form completed and signed at least annually.






Carbamazepine is licensed for the treatment of bipolar disorder in people who are intolerant of lithium or for whom lithium is ineffective. If a service user on carbamazepine presents with mania, the dose should not be routinely increased – an antipsychotic should be considered. Interactions are common and dose adjustment may be required.

Long-term treatment should be discussed with the service user/carer within 4 weeks of resolution of symptoms. If appropriate, treatment for acute episodes can continue for a further 3–6 months, and then should be reviewed.

Bipolar Depression

People with bipolar depression should be offered an evidence-based psychological intervention developed specifically for bipolar disorder or a high-intensity psychological intervention, such as cognitive behavioural therapy, interpersonal therapy or behavioural couples therapy, and monitored for clinical signs of mania or hypomania or deterioration of depressive symptoms.

People who develop moderate or severe bipolar depression and are not taking a drug to treat their bipolar disorder should be offered fluoxetine combined with olanzapine or quetiapine on its own, depending on preference and previous response. If preferred, olanzapine without fluoxetine or lamotrigine can be considered. If there is no response to fluoxetine combined with olanzapine, or quetiapine, consider lamotrigine on its own.

People already taking lithium should have their plasma lithium levels checked and the dose optimised. If the lithium level is at its maximum and response inadequate, fluoxetine combined with olanzapine or quetiapine should be added. Alternatively, adding olanzapine or lamotrigine to lithium may be considered. If there is no response to adding fluoxetine combined with olanzapine, or adding quetiapine, stop the additional treatment and consider adding lamotrigine to lithium.

People already taking valproate, should have their dose increased within the therapeutic range, as tolerated. If there is a limited response to optimal doses of valproate, fluoxetine combined with olanzapine or quetiapine should be added, depending on the person’s preference and previous response to treatment. If the person prefers, consider adding olanzapine (without fluoxetine) or lamotrigine to valproate. If there is no response to adding fluoxetine combined with olanzapine, or adding quetiapine, stop the additional treatment and consider adding lamotrigine to valproate.

Antidepressant medication should only be prescribed in bipolar depression as an adjunct to mood stabilisers, e.g. lithium or valproate or lamotrigine or olanzapine due to risk of switching and cycle acceleration. Such risks may be less with SSRIs.

Bipolar Disorder – Long-Term Treatment

NICE recommends that long-term treatment should be discussed with the service user/carer, within 4 weeks of resolution of each episode of mania or bipolar depression

Selection of long-term pharmacological treatment to prevent relapse should take into account drugs that have been effective during acute episodes of mania or bipolar depression

Lithium should be offered as a first-line, long-term pharmacological treatment. If lithium is ineffective, NICE recommends considering adding valproate.

If lithium is poorly tolerated or is not suitable, consider valproate or olanzapine instead, or quetiapine, if it has been effective during an episode of mania or bipolar depression.

A structured psychological intervention (individual, group or family) designed for bipolar disorder is recommended as part of long term management.

Long term monotherapy or combination treatments should be continued as long as clinically appropriate. If stopping long-term treatment, this should be done gradually and the patient monitored for relapse for 2 years after medication has stopped entirely.



Rapid-Cycling Bipolar Disorder

Rapid-cycling bipolar disorder is defined as the experience of at least four syndromal depressive, manic, hypomanic or mixed episodes within a 12-month period

NICE states that people with rapid cycling bipolar disorder should be offered the same interventions as people with other types of bipolar disorder.

Pharmacological Treatment of Rapid-Cycling Bipolar Disorder

Treatment should be as for manic and depressive episode. In addition: o Review the service user’s previous treatments for bipolar disorder and optimise treatment

doses and long-term treatment o Consider a further trial of any that were not given an adequate trial or not adhered to. o If the person is taking an antidepressant, ensure mood stabilizer is also prescribed.

Consider withdrawing this due to increase risk of cycling. o A psychological intervention that has been developed specifically for bipolar disorder or a

high-intensity psychological intervention should be offered. o Identify and manage possible precipitants for example drug and alcohol problems, thyroid

dysfunction, other stressors etc.

Relevant NICE guidance

NICE CG185 (September 2014): Bipolar disorder: the assessment and management of bipolar

disorder in adults, children and young people in primary and secondary care. http://www.nice.org.uk/guidance/cg185

NICE TA292 (July 2013): Aripiprazole for treating moderate to severe manic episodes in adolescents with bipolar 1 disorder. http://www.nice.org.uk/guidance/ta292

NICE pathways: Bipolar Disorder. http://pathways.nice.org.uk/pathways/bipolar-disorder

NICE Clinical Knowledge Summary: Bipolar Disorder. https://cks.nice.org.uk/bipolar-disorder

Local Shared Care Agreements

1. Shared Care Lithium guideline – Pan Mersey Area.

http://www.panmerseyapc.nhs.uk/shared_care/documents/SC8.pdf

http://www.nice.org.uk/guidance/cg185

http://www.nice.org.uk/guidance/ta292

http://pathways.nice.org.uk/pathways/bipolar-disorder

https://cks.nice.org.uk/bipolar-disorder

http://www.panmerseyapc.nhs.uk/shared_care/documents/SC8.pdf

Mersey Care Clinical Guideline/Formulary Document Reviewed: Jan 2017 (Updated September 2018)

Bipolar Affective Disorder Next Review: Jan 2019 7

Bipolar Affective Disorder – Acute Treatment for Mania/Hypomania

First Line: Relative Cost Notes

Oral antipsychotics Haloperidol Risperidone Tabs/Liquid Orodispersible

Branded Olanzapine Tabs/orodispersible

Branded/Velotab Quetiapine Tabs

M/R Branded

Aripiprazole Tabs Orodispersible Branded / Liquid

£ £ ££ ££-£££ £ £££/££££ £ ££-£££ £££ £ ££ £££

Consider for service users taking an antidepressant; those not taking an antipsychotic or mood stabiliser and those already taking lithium or valproate at optimal doses. Check plasma lithium levels to optimise treatment. Antipsychotics can achieve rapid control of mania. Before prescribing, consider advance statements, preference, side effects and individual risk factors e.g. diabetes, weight gain, adherence and previous response. Monitor, as above. If prescribed antidepressant, consider stopping due to risk of switching and more frequent cycling. *Aripiprazole is recommended by NICE TA292 as an option (for up to 12 weeks). for moderate to severe manic episodes in young people aged 13 and older with bipolar I disorder *Consider risk of movement disorders (EPSE) and tolerability with haloperidol. Special liquids (eg quetiapine liquid) cost significantly more.

Second Line: Relative Cost Notes

Try alternative antipsychotic

£-£££ Consider an alternative antipsychotic not tried from the above list if the first antipsychotic is poorly tolerated at any dose (including rapid weight gain) or if ineffective at the maximum licensed dose. Take into account previous response to treatment and side effects.

Add lithium £-£££

Consider lithium if alternative antipsychotic is not tolerated at optimal dose. Lithium has a slower onset of action. Consider if compliant with blood monitoring (see cautions and notes on lithium, above)

Add Valproate Depakote

£-£££ £££

Consider if lithium is not suitable; Monitoring, see notes above. Teratogenic - Do not prescribe in pregnancy or for girls or women of child-bearing potential. Use adequate contraception. ** See MHRA Drug Safety Update ** Valproate medicines must not be used in women or girls of childbearing potential unless a Pregnancy Prevention Programme is in place. Women or girls or childbearing potential prescribed valproate should have a Risk Acknowledgement Form completed and signed at least annually.

https://www.gov.uk/drug-safety-update/valproate-medicines-epilim-depakote-contraindicated-in-women-and-girls-of-childbearing-potential-unless-conditions-of-pregnancy-prevention-programme-are-met




Bipolar Affective Disorder – Acute Treatment for Mania/Hypomania - Continued

Other Relative Cost Notes

Benzodiazepines e.g. Lorazepam Clonazepam

£ £

Use PRN for as short time as possible; Consider for severe anxiety and agitation present or if sleep deprived. Benzodiazepines can rapidly diminish overactivity but carry a risk of disinhibited behaviour, withdrawal symptoms, tolerance and dependence. They can also cause sedation, ataxia and falls.

Carbamazepine Tabs Liquid / Brand

£ £-££

Should not be used routinely for acute mania; Licensed for people who are intolerant of lithium or for whom lithium is ineffective; Difficult to use- slow dose initiation; numerous side effects and interactions involving enzyme induction; Teratogenic – avoid in girls or women of child-bearing potential

Asenapine ££££ Consultant initiation only by written request to the Chief Pharmacist. Risk of serious hypersensitivity reactions including anaphylactic/anaphylactoid reactions, angioedema, swollen tongue and swollen throat (pharyngeal oedema). Asenapine S/L tablet has anaesthetic properties, patients should be warned of oral numbness/tingling may occur within an hour after administration. Risk of photosensitisation may occur with higher dosages, patients should avoid direct sunlight.

ECT £££ NICE TA 59 recommends that ECT is used only for prolonged or severe manic episode to achieve rapid and short-term improvement of severe symptoms when an adequate trial of other treatment options has proven ineffective, and/or the individual has a potentially life-threatening condition

Not Recommended Relative Cost Notes

Lamotrigine, Topiramate, Gabapentin

£-£££ Do not offer lamotrigine to treat mania. There is inadequate supporting evidence of the effectiveness of topiramate and gabapentin as treatments for bipolar disorder.



Bipolar Affective Disorder – Acute Depressive Episode


Fluoxetine+Olanzapine OR Quetiapine OR Olanzapine OR Lamotrigine Tabs Orodispersible Brand

£-£££ £-£££ £-£££ £ ££ £££

All service users with moderate or severe bipolar depression who are not taking any medication to treat their bipolar disorder should be treated with fluoxetine combined with olanzapine or quetiapine on its own depending on personal preference and previous response. Alternatively, olanzapine without fluoxetine or lamotrigine on its own can be considered if preferred. If there is no response to fluoxetine combined with olanzapine, or quetiapine, consider lamotrigine on its own


Lithium + olanzapine+fluoxetine OR Lithium +Quetiapine OR Lithium + Olanzapine OR Lithium +Lamotrigine

££-£££ £-£££ £-£££ £-£££

If service user is already on lithium as a prophylactic agent check levels and optimise dose. If dose is optimal and limited response, add fluoxetine combined with olanzapine or add quetiapine. Alternatively, add olanzapine (without fluoxetine) or lamotrigine to lithium may be considered. If there is no response to adding fluoxetine combined with olanzapine, or adding quetiapine, stop the additional treatment and consider adding lamotrigine to lithium.

Valproate + olanzapine+fluoxetine OR quetiapine OR Olanzapine OR Lamotrigine

££-£££ £-£££ £-£££ £-£££

If service user is already on valproate, increase dose within the therapeutic range, as tolerated. If there is a limited response to optimal doses of valproate, fluoxetine combined with olanzapine or quetiapine alone should be added, depending on the person’s preference and previous response to treatment. If the person prefers, consider adding olanzapine (without fluoxetine) or lamotrigine to valproate. If there is no response to adding fluoxetine combined with olanzapine, or adding quetiapine, stop the additional treatment and consider adding lamotrigine to valproate.

Be aware of potential interactions between Valproate and fluoxetine, lamotrigine and olanzapine.

** Take into account toxicity in overdose when prescribing psychotropic medication during periods of high suicide risk** Assess need to limit the quantity of

medication supplied to reduce the risk to life if the person overdoses **



Bipolar Affective Disorder – Acute Depressive Episode, continued

Other Relative Cost Notes

Antidepressants £-£££

Antidepressant medication should only be prescribed in bipolar depression as an adjunct to mood stabilisers, e.g. lithium or valproate or lamotrigine or olanzapine due to risk of switching and cycle acceleration. Such risks may be less with SSRIs/SNRIs. Avoid tricyclics or MAOIs. Check side effects and interactions. **Consider stopping the antidepressant if in remission from depressive symptoms

Psychological Interventions

£££ Use of evidence-based psychological interventions developed specifically for bipolar disorder or high-intensity psychological interventions (e.g. cognitive behavioural therapy, interpersonal therapy or behavioural couples therapy) is recommended by NICE. Discuss with the person the possible benefits and risks of psychological interventions and their preference. People receiving psychological interventions should be monitored for clinical signs of mania or hypomania or deterioration of depressive symptoms.

Not Recommended Relative Cost Notes

Topiramate, Gabapentin

£-££ Do not prescribe as there is inadequate supporting evidence of the effectiveness of topiramate and gabapentin as treatments for bipolar disorder,



Bipolar Affective Disorder – Long Term Maintenance Therapy (Relapse Prevention)


NICE recommends that long-term treatment should be discussed with the service user/carer, within 4 weeks of resolution of each episode of mania or bipolar depression Long-term pharmacological treatment to prevent relapse should take into account drugs that have been effective during acute episodes of mania or bipolar depression. The potential benefits of long term treatment and risks, including side effects of medication used should be discussed with the service user.

Lithium OR

£

Lithium should be offered as a first-line, long-term pharmacological treatment; It reduces the risk of relapse, suicidal behavior, self harm and mortality. Monitor level (low therapeutic index), adverse effects and be aware of the risk of rebound phenomena (see notes above).

Lithium +Valproate ££-£££ If lithium is ineffective, NICE recommends considering adding valproate.


Valproate OR Olanzapine

£-£££ If lithium is poorly tolerated or is not suitable ( i.e. because the person does not agree to routine blood monitoring) , consider valproate or olanzapine

Quetiapine £-£££ Consider quetiapine if lithium is poorly tolerated or is not suitable and quetiapine was effective during an acute episode of mania or bipolar depression.

Other: Relative Cost Notes

Psychological therapy £££ A structured psychological intervention (individual, group or family) designed for bipolar disorder which has a published evidence base manual outlining its delivery is recommended as part of long term management to prevent relapse or for people who have some persistent symptoms between episodes of mania and bipolar depression.

Other antipsychotics £-£££ Consider licensed indication, patients preference, previous response and side effect profile Consider clozapine for treatment-refractory symptoms (off-label use)

Antidepressants £-£££ Consider long-term treatment with SSRI and mood stabiliser for chronic recurrent depression



Appendix 1

Drugs Used in Bipolar Disorders

Drug; Licensed Indications

Dose Contraindications and Cautions Side Effects and Interactions

Lithium (Priadel) Formulation Tablets m/r, lithium carbonate 200mg and 400mg Liquid, sugar-free, lithium citrate 520mg/5ml (5mL dose is equivalent to 204mg lithium carbonate) Licensed indications Prophylaxis of bipolar affective disorder and Treatment of acute manic or hypomanic episodes.

Dose range for treatment and prophylaxis is 400-1200mg daily as a single dose or in 2 divided doses (if elderly or < 50kg, (Reduce initial dose - 200mg-400mg daily).

Dose adjusted to achieve lithium levels in the range of 0.4–1mmol/l. Sample taken at least 12 hours. Monitoring schedule after the last dose. Levels should not exceed 1.5mmol/l.

Optimal serum lithium levels may vary for each service user.

Additional serum-lithium levels should be made if significant intercurrent disease or change in sodium or fluid intake.

Preparations vary widely in bioavailability; changing the preparation requires the same precautions as initiating treatment

Discontinue gradually

Contraindications - Hypersensitivity to lithium or excipients - Cardiac disease - Cardiac insufficiency - Severe renal impairment - Untreated hypothyroidism - Breast-feeding - Hyponatraemia, including due to dehydration or low sodium diets - Addison's disease - Brugada syndrome or family history of Brugada syndrome.

Cautions - Renal and thyroid dysfunction, - Electrolyte imbalance/diuretics - Cardiac problems - Psoriasis - Seizures - QT interval prolongation - Elderly people - drug interactions - Low sodium diet - Dehydration, diarrhoea, vomiting

Side effects Lithium has a narrow therapeutic index.

Side effects are related to serum levels, as follows: - Mild gastrointestinal side effects such as nausea, abdominal discomfort and taste disorder - Tremor, especially fine hand tremors - Peripheral oedema and weight gain - Hyperglycaemia, - Leucocytosis - Confusion - Reduction in thyroid and renal function - Polydipsia and/or polyuria - Sexual dysfunction

High serum-lithium levels (usually >1.5mmol/litre) can cause toxic effects including restlessness, apathy, nausea, coarse tremor, vomiting, diarrhoea, drowsiness, blurred vision, ataxia, dysarthria, myalgia and arthralgia. Lithium should be stopped. Higher levels can lead to confusion, hyperreflexia, renal failure, convulsions, coma and death.

Long-term adverse effects may include thyroid function disturbances such as euthyroid goitre and/or hypothyroidism and thyrotoxicosis.

Key interactions: NSAIDs; Diuretics e.g. thiazides, ACE Inhibitors; Angiotensin II antagonists, calcium channel blockers, additive effect with psychotropic drugs




Drug Licensed Indications


Valproate Depakote: tablets 250mg; 500mg Episenta capsules 150mg, 300mg (Other valproate preparations are also used off label) Licensed indications Treatment of manic episodes associated with bipolar disorder when lithium is contraindicated or not tolerated. The continuation of treatment after manic episode could be considered in patients who have responded to sodium valproate for acute mania. Prophylaxis of bipolar disorder in patient who responded to valproate in acute phase.

Initial dose: 750 mg daily in 2–3 divided doses, increased according to response. Maintenance dose: 1–2g daily Doses greater than 45mg/kg daily require careful monitoring See above for monitoring schedule

Contraindications Active liver disease; family history of severe hepatic dysfunction; acute porphyria; Pregnancy; Valproate is contraindicated in females of childbearing potential unless the conditions of the pregnancy prevention programme are met Cautions Valproate has a high teratogenic potential and children exposed in utero to valproate have a high risk for congenital malformations and neurodevelopmental disorders. Monitor liver function before therapy and during first 6 months especially in those most at risk; Measure full blood count and ensure no undue potential for bleeding before starting and before surgery Systemic lupus erythematosus; False-positive urine tests for ketones; Avoid abrupt withdrawal; Consider vitamin D supplementation in patients that are immobilised for long periods or who have inadequate sun exposure or dietary intake of calcium

Side effects Gastrointestinal disturbances, particularly at the start of therapy. Increased appetite, and weight gain is common. Less common adverse effects include oedema, headache, reversible prolongation of bleeding time, and thrombocytopenia. Leucopenia and bone marrow depression have been reported. Tremor and ataxia have also been reported usually when therapy is started. Transient hair loss. Occasionally rashes. Rare but serious side effect are liver damage and pancreatitis Interactions Caution is recommended when giving valproate with other drugs liable to interfere with blood coagulation, such as aspirin or warfarin. Use with other hepatotoxic drugs should be avoided. Use of highly protein bound drugs with valproate may increase free valproate plasma concentrations. Care with dosing when used with lamotrigine Potential for additive effects when used with other psychotropic drugs






Carbamazepine Tablets 100mg, 200mg and 400mg; Prolonged Release 200mg and 400mg Tablets; Liquid 100 mg/5ml Licensed indications Prophylaxis of bipolar disorder unresponsive to lithium

Initial dose: 400mg daily in divided doses Maintenance dose: 400–600mg daily; max. 1.6g daily

Contraindications: AV conduction abnormalities (unless paced); history of bone-marrow depression; acute porphyria; known hypersensitivity to carbamazepine or structurally related drugs (e.g. tricyclic antidepressants) Not recommended in combination with monoamine oxidase inhibitors (MAOIs) Cautions Cardiac disease. History of haematological reactions to other drugs. Susceptibility to angle-closure glaucoma Liver dysfunction or acute liver disease. Manufacturer recommends blood counts and hepatic and renal function tests Plasma monitoring is required to exclude toxicity

Side effects Common side effects include dizziness and ataxia; gastrointestinal disturbances e.g. nausea and vomiting; blurred vision; hypertension and hypotension; mild skin reactions and transient leucopenia - Serious dermatologic side effects include generalised erythematous rashes Stevens-Johnson syndrome and toxic epidermal necrolysis. Risk greater in in people of Thai or Han Chinese, Japanese or European descent. - Blood disorders reported include eosinophilia, leucopenia, thrombocytopenia, haemolytic anaemia, and anaemia. - Also reported are hepatitis, jaundice, pancreatitis - Abnormalities of kidney function and cardiac conduction disorders. Congestive heart failure. Hyponatraemia have occurred. - Exacerbation of seizures - Congenital malformations have been reported in infants born to women given carbamazepine during pregnancy

Interactions - Carbamazepine is a hepatic enzyme inducer, and induces its own metabolism as well as that of other drugs including antibacterials (e.g. doxycycline), anticoagulants, and sex hormones (notably oral contraceptives) reducing therapeutic effect. - Drugs that induce CYP3A4 may increase the metabolism of carbamazepine, - May interact with MAOIs, other antiepileptics/ mood stabilisers.






Lamotrigine (non-proprietary) or Lamictal Licensed Indication Adults aged 18 years and above - Prevention of depressive episodes in patients with bipolar I disorder who experience predominantly depressive episodes

Monotherapy OR adjunctive therapy of bipolar disorder without valproate AND without enzyme inducing drugs* initially 25mg once daily for 14 days, then 50mg daily in 1–2 divided doses for further 14 days, then 100mg daily in 1–2 divided doses for further 7 days; usual maintenance 200mg daily in 1–2 divided doses; max. 400mg daily Adjunctive therapy of bipolar disorder with valproate, initially 25mg on alternate days for 14 days, then 25mg once daily for further 14 days, then 50mg daily in 1–2 divided doses for further 7 days; usual maintenance 100mg daily in 1–2 divided doses; max. 200mg daily Adjunctive therapy of bipolar disorder without valproate WITH enzyme inducing drugs* initially 50mg once daily for 14 days, then 50mg twice daily for further 14 days, then 100mg twice daily for further 7 days, then 150mg twice daily for further 7 days; usual maintenance 200mg twice daily dose adjustments may be required if other drugs are added to or withdrawn from their treatment regimen

Contraindications Hypersensitivity to the active substance or to any of the excipients Cautions Skin reactions - monitor and withdrawal if rash, fever, or other signs of hypersensitivity syndrome develop Increases clearance of hormonal contraceptive Parkinson’s disease - risk of exacerbation Blood disorders Renal/hepatic impairment Suicidal risk

Skin rash Nausea, vomiting, diarrhoea, dry mouth Aggression, irritability, agitation Headache Somnolence, dizziness, tremor, insomnia, Arthralgia, tiredness, pain, back pain Nystagmus, diplopia, blurred vision, hypersensitivity syndrome Blood disorders

* phenytoin, carbamazepine, phenobarbitone, primidone, rifampicin, lopinavir/ritonavir




Drug; Licensed Indication Dose Contraindications and Cautions*

Side Effects and Interactions*

Antipsychotics Quetiapine - oral Manic episodes; major depressive episodes in bipolar disorders; prevention of bipolar disorder when response in acute phase Olanzapine – oral Moderate to severe manic episode; prevention of manic episode when response in acute phase Aripiprazole – oral Moderate to severe manic episodes; prevention of manic episode Risperidone – oral Moderate to severe manic episodes Haloperidol – oral Mania and hypomania Asenapine- S/L moderate to severe manic episodes

Usual range 400–800 mg daily in 2 divided doses. Treatment of bipolar depression max 600mg daily. 15 mg daily adjusted to usual range of 5–20 mg. Max. 20mg 15 mg once daily, increased if necessary; max. 30 mg once daily 2 mg once daily, increased if necessary by1 mg daily; max 6 mg daily 2–20 mg daily as single or divided doses, maintenance 1–3 mg three times daily max. 20 mg daily (in divided doses); Starting dose 5 mg twice daily. May be increased to 10 mg twice daily.

Contraindications: - Comatose states, - CNS depression - Phaeochromocytoma Cautions: - Cardiovascular disease - Elderly patients with dementia - Parkinson's disease - Epilepsy - Depression - Myasthenia gravis - Prostatic hypertrophy - Angle-closure glaucoma - Severe respiratory disease - History of jaundice - History of blood dyscrasias - Photosensitisation may occur with higher dosages. - Dependence and withdrawal reactions

Side effects - Gastrointestinal adverse effects—including constipation, dry mouth, nausea - Central nervous system adverse effects including sedation and sleep disturbances - Extrapyramidal side effects—acute dystonia, akathisia, parkinsonism, tardive dyskinesia - Neuroleptic malignant syndrome - Convulsions - Cardiovascular adverse effects - Blood pressure changes - Cerebrovascular events - Cardiac rhythm disorders particularly QT prolongation - Venous thromboembolism - Metabolic adverse effects—including weight gain, dyslipidaemia, hyperglycaemia - Hyperprolactinaemia and sexual adverse effects—including menstrual and sexual dysfunction, osteoporosis - Blood disorders—including neutropenia, agranulocytosis - Temperature regulation—hypothermia and hyperthermia - Adverse effects on the skin—including rash, pruritus - Adverse effects on the eye—including precipitation of glaucoma, mydriasis, and pigmentation - Antimuscarinic adverse effects—including constipation, nasal stuffiness, and urinary retention Drug interactions of concern include interactions which increase adverse effects (hypotension, sedation, cardiac rhythm disturbances)

*See schizophrenia formulary for comparative side effects of antipsychotics



Appendix 2: Schedule for Physical Monitoring for People with Bipolar Disorder

Adapted from NICE CG38 – Bipolar Disorder and Updated in line with NICE CG185

Monitoring for all patients Monitoring for specific drugs

Test or measurement

Initial health check

6 months Annual check up

Antipsychotics Lithium Valproate* Carbamazepine Lamotrigine

Thyroid function

Yes Yes Yes; 6 monthly if rapid cycling

At start and every 6 months; more often if evidence of deterioration

Liver function Yes Yes If clinically relevant

At start and at 6 months and repeat annually

At start and at 6 months

At start

Renal function/ eGFR U&Es including Calcium

Yes Yes Yes If clinically relevant

At start and every 6 months; more often if there is evidence of deterioration of the patient or if they start taking drugs such as ACE inhibitors, diuretics or NSAIDs

Urea and electrolytes every 6 months

At start

Full blood count

Yes If clinically relevant. Mandatory for clozapine

A start of treatment At start and at 6 months and repeat annually

At start and at 6 months

At start

Blood (plasma) glucose fasting or HbA1c

Yes Yes At start and at 12 weeks; more often if evidence of elevated levels

Lipid profile Yes Yes At start and at 12 weeks; more often if elevated levels



Monitoring for all patients Monitoring for specific drugs

Test or measurement


6 months Annual check up


Blood pressure/ Pulse

Yes Yes At start and at each dose change

Prolactin Yes If symptoms of raised prolactin develop

ECG If indicated by history or clinical picture

If indicated by history or clinical picture

At start if specified by license; if there are risk factors for, history of or existing cardio-vascular disease or if an inpatient

At start, especially if risk factors for or existing cardiovascular disease

Weight/height BMI

Yes

Yes Yes weekly for the first 6 weeks, then at 12 weeks; more often if patient gains weight rapidly

At start then every 6 months or more if the patient gains weight rapidly

At start and at 6 months and repeat annually; more often if patient gains weight rapidly

At start and at

6 months if the

patient gains

weight rapidly

Diet Nutritional Status

Dietary advice Dietary and fluid intake advice

Physical Activity

Yes Yes At start then annually



Monitoring for all patients

Monitoring for specific drugs

Test or measurement


Annual check up


Drug screening and chest X-ray

If suggested by the history or clinical picture

EEG, MRI, CT scans

If organic aetiology or comorbidity is suspected

Smoking/ alcohol

Yes Yes

Serum levels of drug

1 week after initiation and every 5-7 days after every dose change until levels stable, then every 3 months for the first year then 3-6 months depending on risk factors

Only if there is evidence of ineffectiveness or poor adherence or toxicity

If clinically relevant



References

2. NICE CG185 (September 2014): Bipolar disorder: the assessment and management of bipolar disorder in adults, children and young people in primary and secondary care. http://www.nice.org.uk/guidance/cg185

3. NICE TA292 (July 2013): Aripiprazole for treating moderate to severe manic episodes in adolescents with bipolar 1 disorder. http://www.nice.org.uk/guidance/ta292

4. NICE QS95 (2015): Bipolar disorder in adults. http://www.nice.org.uk/guidance/qs95

5. British Association for Psychopharmacology. G. M Goodwin, Consensus Group of the British Association for Psychopharmacology. Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology. Journal of Psychopharmacology (2016) 1-59. Available at: https://www.bap.org.uk/pdfs/BAP_Guidelines-Bipolar.pdf

6. MHRA (2018). Valproate use by women and girls. Information about the risks of taking valproate medicines during pregnancy. https://www.gov.uk/guidance/valproate-use-by-women-and-girls. Updated August 2018

7. MHRA (2018) Valproate medicines: contraindicated in women and girls of childbearing potential unless conditions of Pregnancy Prevention Programme are met https://www.gov.uk/drug-safety-update/valproate-medicines-epilim-depakote-contraindicated-in-women-and-girls-of-childbearing-potential-unless-conditions-of-pregnancy-prevention-programme-are-met#conditions-and-guidance-for-the-pregnancy-prevention-programme. Update May 2018

8. MHRA (2018) Valproate banned without the pregnancy prevention programme. https://www.gov.uk/government/news/valproate-banned-

without-the-pregnancy-prevention-programme.

9. BNF online at: https://bnf.nice.org.uk/

10. Martindale – The complete drug reference online at: https://about.medicinescomplete.com/#/ [subscription required]

11. Product SPCs for drugs referred to in this guideline can be found in the Electronic Medicines Compendium (http://emc.medicines.org.uk/).

Mersey Care NHS Foundation Trust. Guidelines for the Prescribing, Supply and Monitoring of Lithium Therapy. Available at:

http://sharepoint.merseycare.nhs.uk/sites/LocalServices/PharmacyServices/Shared%20Documents/Safer%20Medication%20Practice%20Alerts

/Lithium_Guidelines_%202017.pdf.

12. Pan Mersey Shared Care Framework for Lithium in Adults. https://www.panmerseyapc.nhs.uk/media/2018/lithium_201809_v0400.pdf

http://www.nice.org.uk/guidance/cg185

http://www.nice.org.uk/guidance/ta292

http://www.nice.org.uk/guidance/qs95

https://www.bap.org.uk/pdfs/BAP_Guidelines-Bipolar.pdf

https://www.gov.uk/guidance/valproate-use-by-women-and-girls

https://www.gov.uk/drug-safety-update/valproate-medicines-epilim-depakote-contraindicated-in-women-and-girls-of-childbearing-potential-unless-conditions-of-pregnancy-prevention-programme-are-met#conditions-and-guidance-for-the-pregnancy-prevention-programme



https://www.gov.uk/government/news/valproate-banned-without-the-pregnancy-prevention-programme

https://www.gov.uk/government/news/valproate-banned-without-the-pregnancy-prevention-programme

https://bnf.nice.org.uk/

http://emc.medicines.org.uk/

http://sharepoint.merseycare.nhs.uk/sites/LocalServices/PharmacyServices/Shared%20Documents/Safer%20Medication%20Practice%20Alerts/Lithium_Guidelines_%202017.pdf

http://sharepoint.merseycare.nhs.uk/sites/LocalServices/PharmacyServices/Shared%20Documents/Safer%20Medication%20Practice%20Alerts/Lithium_Guidelines_%202017.pdf

https://www.panmerseyapc.nhs.uk/media/2018/lithium_201809_v0400.pdf