Clinical Guideline/Formulary Document - Pharmacy Department Medicines Management Services - Mersey Care NHS Foundation
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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. Mersey Care Clinical Guideline/Formulary Document Updated: Jan 2019 Bipolar Affective Disorder Next Review: Jan 2021 1|
Be aware of potential interactions of between mood stabilisers, antipsychotics and
antidepressants used for bipolar disorder and also with other prescribed medication.
For advice on DRIVING and health conditions, see DVLA.
It is illegal to drive if medication impairs driving ability. See Drugs and driving: the law.
It is an offence for a person to drive with certain levels of some medications in the blood.
See https://www.gov.uk/government/collections/drug-driving#table-of-drugs-and-limits
for up to date information.
A guide to support medical professionals in assessing fitness to drive can be found at
https://www.gov.uk/government/publications/assessing-fitness-to-drive-a-guide-for-
medical-professionals
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 stabilised
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.
Mersey Care Clinical Guideline/Formulary Document Updated: Jan 2019
Bipolar Affective Disorder Next Review: Jan 2021 2|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.
https://webarchive.nationalarchives.gov.uk/20100312174238/http://www.nrls.nps
a.nhs.uk/resources/search-by-audience/community-pharmacy-
staff/?entryid45=65426&cid=898358&p=1
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%.
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.
Teratogenicity: Possible increase risk of cardiac defects and neonatal complications.
Avoid in pregnancy and women planning pregnancy.
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 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 of childbearing potential prescribed valproate should have
a Risk Acknowledgement Form completed and signed at least annually. See MHRA
drug safety alert.
The Valproate Pregnancy Prevention Programme is supported by a Patient Guide, a
Guide for Healthcare Professionals, Annual Risk Acknowledgement Form, a Patient
Card and Stickers with warning symbols. See MHRA guidance.
Be aware of potential interactions between valproate and other mood stabilisers
particularly carbamazepine and lamotrigine, olanzapine and fluoxetine.
Mersey Care Clinical Guideline/Formulary Document Updated: Jan 2019
Bipolar Affective Disorder Next Review: Jan 2021 3|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 – Increase risk of developmental disorders and congenital
malformations.
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.
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
Teratogenicity – Lamotrigine is a folic antagonist and may increase the risk of
orofacial clefting. High dose (5mg daily) folic acid is recommended
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 disorder.
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 (PPP) 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.
Mersey Care Clinical Guideline/Formulary Document Updated: Jan 2019
Bipolar Affective Disorder Next Review: Jan 2021 4|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 acute manic or depressive 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 of 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. Mersey Care Clinical Guideline/Formulary Document Updated: Jan 2019 Bipolar Affective Disorder Next Review: Jan 2021 5|
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. Follow recommendations above
on valproate and pregnancy.
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.
Mersey Care Clinical Guideline/Formulary Document Updated: Jan 2019
Bipolar Affective Disorder Next Review: Jan 2021 6|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 Local Shared Care Agreements Shared Care Lithium guideline – Pan Mersey Area. https://www.panmerseyapc.nhs.uk/media/2083/lithium_sharedcare.pdf Mersey Care Clinical Guideline/Formulary Document Updated: Jan 2019 Bipolar Affective Disorder Next Review: Jan 2021 7|
Bipolar Affective Disorder – Acute Treatment for Mania/Hypomania
First Line: Relative Cost Notes
Oral antipsychotics Consider for service users taking an antidepressant; those not taking an antipsychotic or mood stabiliser
Haloperidol £ and those already taking lithium or valproate at optimal doses. Check plasma lithium levels to optimise
Risperidone treatment. Antipsychotics can achieve rapid control of mania. Before prescribing, consider advance
Tabs/Liquid £ statements, preference, side effects and individual risk factors e.g. diabetes, weight gain, adherence and
Orodispersible ££ previous response. Monitor, as above.
Branded ££-£££ If prescribed antidepressant, consider stopping due to risk of switching and more frequent cycling.
Olanzapine *Aripiprazole is recommended by NICE TA292 as an option (for up to 12 weeks). for moderate to severe
Tabs/orodispersible £ manic episodes in young people aged 13 and older with bipolar I disorder
Branded/Velotab £££/££££ *Consider risk of movement disorders (EPSE) and tolerability with haloperidol.
Quetiapine Special liquids (eg quetiapine liquid) cost significantly more.
Tabs £
M/R ££-£££
Branded £££
Aripiprazole
Tabs £
Orodispersible ££
Branded / Liquid £££
Second Line: Relative Cost Notes
Try alternative £-£££ Consider an alternative antipsychotic not tried from the above list if the first antipsychotic is poorly tolerated
antipsychotic 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 £-£££ Consider if lithium is not suitable; Monitoring, see notes above. Teratogenic - Do not prescribe for girls or
Depakote £££ women of child-bearing potential. Use adequate contraception. ** See MHRA warning ** 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.
Mersey Care Clinical Guideline/Formulary Document Updated: Jan 2019
Bipolar Affective Disorder Next Review: Jan 2021 8Bipolar Affective Disorder – Acute Treatment for Mania/Hypomania - Continued
Other Relative Cost Notes
Benzodiazepines e.g. Use PRN for as short time as possible; Consider for severe anxiety and agitation present or if sleep
Lorazepam £ deprived. Benzodiazepines can rapidly diminish overactivity but carry a risk of disinhibited behaviour,
Clonazepam £ withdrawal symptoms, tolerance and dependence. They can also cause sedation, ataxia and falls.
Carbamazepine Should not be used routinely for acute mania; Licensed for people who are intolerant of lithium or for whom
Tabs £ lithium is ineffective; Difficult to use- slow dose initiation; numerous side effects and interactions involving
Liquid / Brand £-££ 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, £-£££ Do not offer lamotrigine to treat mania. There is inadequate supporting evidence of the effectiveness of
Gabapentin topiramate and gabapentin as treatments for bipolar disorder.
Mersey Care Clinical Guideline/Formulary Document Updated: Jan 2019
Bipolar Affective Disorder Next Review: Jan 2021 9Bipolar Affective Disorder – Acute Depressive Episode First Line: Relative Cost Notes Fluoxetine+Olanzapine £-£££ All service users with moderate or severe bipolar depression who are not taking any medication to treat OR their bipolar disorder should be treated with fluoxetine combined with olanzapine or quetiapine on its own Quetiapine £-£££ depending on personal preference and previous response. OR Alternatively, olanzapine without fluoxetine or lamotrigine on its own can be considered if preferred. Olanzapine £-£££ If there is no response to fluoxetine combined with olanzapine, or quetiapine, consider lamotrigine on its OR own Lamotrigine Tabs £ Orodispersible ££ Brand £££ Second Line: Relative Cost Notes Lithium + If service user is already on lithium as a prophylactic agent check levels and optimise dose. If dose is olanzapine+fluoxetine ££-£££ optimal and limited response, add fluoxetine combined with olanzapine or add quetiapine. Alternatively, OR add olanzapine (without fluoxetine) or lamotrigine to lithium may be considered. If there is no response to Lithium +Quetiapine £-£££ adding fluoxetine combined with olanzapine, or adding quetiapine, stop the additional treatment and OR consider adding lamotrigine to lithium. Lithium + Olanzapine £-£££ OR Lithium +Lamotrigine £-£££ Valproate + If service user is already on valproate, increase dose within the therapeutic range, as tolerated. If there is olanzapine+fluoxetine ££-£££ a limited response to optimal doses of valproate, fluoxetine combined with olanzapine or quetiapine alone OR should be added, depending on the person’s preference and previous response to treatment. quetiapine £-£££ If the person prefers, consider adding olanzapine (without fluoxetine) or lamotrigine to valproate. OR If there is no response to adding fluoxetine combined with olanzapine, or adding quetiapine, stop the Olanzapine £-£££ additional treatment and consider adding lamotrigine to valproate. OR Lamotrigine £-£££ 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 ** Mersey Care Clinical Guideline/Formulary Document Updated: Jan 2019 Bipolar Affective Disorder Next Review: Jan 2021 10
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 £££ Use of evidence-based psychological interventions developed specifically for bipolar disorder or high-
Interventions 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, £-££ Do not prescribe as there is inadequate supporting evidence of the effectiveness of topiramate and
Gabapentin gabapentin as treatments for bipolar disorder,
Mersey Care Clinical Guideline/Formulary Document Updated: Jan 2019
Bipolar Affective Disorder Next Review: Jan 2021 11Bipolar Affective Disorder – Long Term Maintenance Therapy (Relapse Prevention)
First Line: Relative Cost Notes
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 £ 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
OR effects and be aware of the risk of rebound phenomena (see notes above).
Lithium +Valproate* ££-£££ If lithium is ineffective, NICE recommends considering adding valproate*.
Second Line: Relative Cost Notes
Valproate* OR £-£££ If lithium is poorly tolerated or is not suitable ( i.e. because the person does not agree to routine
Olanzapine 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
* Follow recommendations above on valproate and pregnancy.
Mersey Care Clinical Guideline/Formulary Document Updated: Jan 2019
Bipolar Affective Disorder Next Review: Jan 2021 12Appendix 1
Drugs Used in Bipolar Disorders
Drug; Dose Contraindications and Cautions Side Effects and Interactions
Licensed
Indications
Lithium (Priadel) Dose range for treatment and Contraindications Side effects
prophylaxis is 400-1200mg daily as a - Hypersensitivity to lithium or Lithium has a narrow therapeutic index.
Formulation single dose or in 2 divided doses (if excipients Side effects are related to serum levels, as follows:
Tablets m/r, lithium elderly or < 50kg, (Reduce initial - Cardiac disease - Mild gastrointestinal side effects such as nausea,
carbonate 200mg and dose - 200mg-400mg daily). - Cardiac insufficiency abdominal discomfort and taste disorder
400mg - Severe renal impairment - Tremor, especially fine hand tremors
Dose adjusted to achieve lithium - Untreated hypothyroidism - Peripheral oedema and weight gain
Liquid, sugar-free, levels in the range of 0.4–1mmol/l. - Breast-feeding - Hyperglycaemia,
lithium citrate Sample taken at least 12 hours. - Hyponatraemia, including due to - Leucocytosis
520mg/5ml Monitoring schedule after the last dehydration or low sodium diets - Confusion
(5mL dose is dose. Levels should not exceed - Addison's disease - Reduction in thyroid and renal function
equivalent to 204mg 1.5mmol/l. - Brugada syndrome or family - Polydipsia and/or polyuria
lithium carbonate) history of Brugada syndrome. - Sexual dysfunction
Optimal serum lithium levels may High serum-lithium levels (usually >1.5mmol/litre)
Licensed indications vary for each service user. Cautions can cause toxic effects including restlessness,
Prophylaxis of bipolar - Renal and thyroid dysfunction, apathy, nausea, coarse tremor, vomiting, diarrhoea,
affective disorder Additional serum-lithium levels - Electrolyte imbalance/diuretics drowsiness, blurred vision, ataxia, dysarthria,
and should be made if significant - Cardiac problems myalgia and arthralgia. Lithium should be stopped.
Treatment of acute intercurrent disease or change in - Psoriasis Higher levels can lead to confusion, hyperreflexia,
manic or hypomanic sodium or fluid intake. - Seizures renal failure, convulsions, coma and death.
episodes. - Pregnancy Long-term adverse effects may include thyroid
Preparations vary widely in - QT interval prolongation
bioavailability; changing the function disturbances such as euthyroid goitre
- Elderly people and/or hypothyroidism and thyrotoxicosis.
preparation requires the same - drug interactions
precautions as initiating treatment Key interactions:
- Low sodium diet
NSAIDs; Diuretics e.g. thiazides, ACE Inhibitors;
- Dehydration, diarrhoea, vomiting
Discontinue gradually Angiotensin II antagonists, calcium channel blockers,
additive effect with psychotropic drugs
Mersey Care Clinical Guideline/Formulary Document Updated: Jan 2019
Bipolar Affective Disorder Next Review: Jan 2021 13Drugs Used in Bipolar Disorders
Drug Dose Contraindications and Cautions Side Effects and Interactions
Licensed
Indications
Valproate Initial dose: 750 mg daily in Contraindications Side effects
Depakote: tablets 2–3 divided doses, increased Active liver disease; family history of Gastrointestinal disturbances, particularly at the start of
250mg; 500mg according to response. severe hepatic dysfunction; acute therapy. Increased appetite, and weight gain is common.
Episenta capsules porphyria; Pregnancy: valproate is Less common adverse effects include oedema, headache,
150mg, 300mg Maintenance dose: 1–2g contraindicated In women of reversible prolongation of bleeding time, and
(Other valproate daily childbearing potential unless the thrombocytopenia. Leucopenia and bone marrow
preparations are also Doses greater than 45mg/kg conditions of the pregnancy depression have been reported. Tremor and ataxia have
used off label) daily require careful prevention programme are met. also been reported usually when therapy is started.
monitoring Transient hair loss. Occasionally rashes. Rare but serious
Licensed indications See above for monitoring Cautions side effect are liver damage and pancreatitis
Treatment of manic schedule Valproate has a high teratogenic
episodes associated potential and children exposed in Interactions
with bipolar disorder utero to valproate have a high risk for Caution is recommended when giving valproate with other
when lithium is congenital malformations and drugs liable to interfere with blood coagulation, such as
contraindicated or not neurodevelopmental disorders. aspirin or warfarin. Use with other hepatotoxic drugs
tolerated. The Monitor liver function before therapy should be avoided. Use of highly protein bound drugs with
continuation of and during first 6 months especially valproate may increase free valproate plasma
treatment after manic in those most at risk; concentrations.
episode could be Measure full blood count and ensure Care with dosing when used with lamotrigine
considered in patients no undue potential for bleeding Potential for additive effects when used with other
who have responded before starting and before surgery psychotropic drugs
to sodium valproate for Systemic lupus erythematosus;
acute mania. False-positive urine tests for ketones;
Prophylaxis of bipolar Avoid abrupt withdrawal;
disorder in patient who Consider vitamin D supplementation
responded to valproate in patients that are immobilised for
in acute phase. long periods or who have inadequate
sun exposure or dietary intake of
calcium
Mersey Care Clinical Guideline/Formulary Document Updated: Jan 2019
Bipolar Affective Disorder Next Review: Jan 2021 14Drugs Used in Bipolar Disorders
Drug; Dose Contraindications and Cautions Side Effects and Interactions
Licensed
Indications
Carbamazepine Initial dose: 400mg daily in Contraindications: Side effects
divided doses AV conduction abnormalities Common side effects include dizziness and ataxia;
Tablets 100mg, 200mg (unless paced); history of bone- gastrointestinal disturbances e.g. nausea and vomiting;
and 400mg; Maintenance dose: 400– marrow depression; acute blurred vision; hypertension and hypotension; mild skin
600mg daily; max. 1.6g daily porphyria; known hypersensitivity to reactions and transient leucopenia
Prolonged Release carbamazepine or structurally - Serious dermatologic side effects include generalised
200mg and 400mg related drugs (e.g. tricyclic erythematous rashes Stevens-Johnson syndrome and toxic
Tablets; antidepressants) epidermal necrolysis. Risk greater in in people of Thai or
Not recommended in combination Han Chinese, Japanese or European descent.
Liquid 100 mg/5ml with monoamine oxidase inhibitors - Blood disorders reported include eosinophilia, leucopenia,
(MAOIs) thrombocytopenia, haemolytic anaemia, and anaemia.
- Also reported are hepatitis, jaundice, pancreatitis
Licensed indications Cautions - Abnormalities of kidney function and cardiac conduction
Prophylaxis of bipolar Cardiac disease. disorders. Congestive heart failure. Hyponatraemia have
disorder unresponsive History of haematological reactions occurred.
to lithium to other drugs. - Exacerbation of seizures
Susceptibility to angle-closure - Neurodevelopment disorders and congenital malformations
glaucoma have been reported in infants born to women given
Liver dysfunction or acute liver carbamazepine during pregnancy
disease.
Manufacturer recommends blood Interactions
counts and hepatic and renal - Carbamazepine is a hepatic enzyme inducer, and induces
function tests its own metabolism as well as that of other drugs including
Plasma monitoring is required to antibacterials (e.g. doxycycline), anticoagulants, and sex
exclude toxicity 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.
Mersey Care Clinical Guideline/Formulary Document Updated: Jan 2019
Bipolar Affective Disorder Next Review: Jan 2021 15Drugs Used in Bipolar Disorders
Drug; Dose Contraindications and Cautions Side Effects and Interactions
Licensed
Indications
Lamotrigine Monotherapy OR adjunctive therapy of bipolar Contraindications Skin rash
(non-proprietary) or disorder without valproate AND without Hypersensitivity to the active Nausea, vomiting, diarrhoea, dry mouth
Lamictal enzyme inducing drugs* substance or to any of the excipients Aggression, irritability, agitation
initially 25mg once daily for 14 days, then Headache
Licensed Indication 50mg daily in 1–2 divided doses for further 14 Cautions Somnolence, dizziness, tremor, insomnia,
Adults aged 18 years days, then 100mg daily in 1–2 divided doses Skin reactions - monitor and Arthralgia, tiredness, pain, back pain
and above for further 7 days; usual maintenance 200mg withdrawal if rash, fever, or other Nystagmus, diplopia, blurred vision,
- Prevention of daily in 1–2 divided doses; max. 400mg daily signs of hypersensitivity syndrome hypersensitivity syndrome
depressive episodes in develop Blood disorders
patients with bipolar I Adjunctive therapy of bipolar disorder with Increases clearance of hormonal
disorder who valproate, initially 25mg on alternate days for contraceptive
experience 14 days, then 25mg once daily for further 14 Parkinson’s disease - risk of
predominantly days, then 50mg daily in 1–2 divided doses for exacerbation
depressive episodes further 7 days; usual maintenance 100mg daily Blood disorders
in 1–2 divided doses; max. 200mg daily Renal/hepatic impairment
Suicidal risk
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
* phenytoin, carbamazepine, phenobarbitone, primidone, rifampicin, lopinavir/ritonavir
Mersey Care Clinical Guideline/Formulary Document Updated: Jan 2019
Bipolar Affective Disorder Next Review: Jan 2021 16Drugs Used in Bipolar Disorders
Drug; Licensed Indication Dose Contraindications and Side Effects and Interactions*
Cautions*
Antipsychotics Contraindications: Side effects
Quetiapine - oral Usual range 400– - Comatose states, - Gastrointestinal adverse effects—including constipation, dry
Manic episodes; major 800 mg daily in 2 - CNS depression mouth, nausea
depressive episodes in bipolar divided doses. - Phaeochromocytoma - Central nervous system adverse effects including sedation
disorders; prevention of bipolar Treatment of bipolar and sleep disturbances
disorder when response in depression max 600mg Cautions: - Extrapyramidal side effects—acute dystonia, akathisia,
acute phase daily. - Cardiovascular disease parkinsonism, tardive dyskinesia
- Elderly patients with dementia - Neuroleptic malignant syndrome
Olanzapine – oral 15 mg daily adjusted to - Parkinson's disease - Convulsions
Moderate to severe manic usual range of 5–20mg. - Epilepsy - Cardiovascular adverse effects
episode; prevention of manic Max. 20mg - Depression - Blood pressure changes
episode when response in - Myasthenia gravis - Cerebrovascular events
acute phase - Prostatic hypertrophy - Cardiac rhythm disorders particularly QT prolongation
- Angle-closure glaucoma - Venous thromboembolism
Aripiprazole – oral 15mg once daily, - Severe respiratory disease - Metabolic adverse effects—including weight gain,
Moderate to severe manic increased if necessary; - History of jaundice dyslipidaemia, hyperglycaemia
episodes; prevention of manic max. 30mg once daily - History of blood dyscrasias - Hyperprolactinaemia and sexual adverse effects—including
episode - Photosensitisation may occur menstrual and sexual dysfunction, osteoporosis
2mg once daily, with higher dosages. - Blood disorders—including neutropenia, agranulocytosis
Risperidone – oral increased if necessary - Dependence and withdrawal - Temperature regulation—hypothermia and hyperthermia
Moderate to severe manic by1mg daily; max 6mg reactions - Adverse effects on the skin—including rash, pruritus
episodes daily - Adverse effects on the eye—including precipitation of
glaucoma, mydriasis, and pigmentation
2–20 mg daily as single - Antimuscarinic adverse effects—including constipation,
Haloperidol – oral or divided doses, nasal stuffiness, and urinary retention
Mania and hypomania maintenance 1–3 mg
three times daily max. Drug interactions of concern include interactions which
20 mg daily (in divided increase adverse effects (hypotension, sedation, cardiac
doses); rhythm disturbances)
Asenapine- S/L Starting dose 5 mg
moderate to severe manic twice daily. May be
episodes increased to 10 mg
twice daily.
*See Psychosis and Schizophrenia clinical guideline document for comparative side effects of antipsychotics
Mersey Care Clinical Guideline/Formulary Document Updated: Jan 2019
Bipolar Affective Disorder Next Review: Jan 2021 17Appendix 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 Initial 6 months Annual Antipsychotics Lithium Valproate* Carbamazepine Lamotrigine
measurement health check up
check
Thyroid Yes Yes Yes; 6 At start and every 6
function monthly if months; more often
rapid if evidence of
cycling deterioration
Liver function Yes Yes If clinically At start and at 6 At start and at 6 At start
relevant months and months
repeat annually
Renal function/ Yes Yes Yes If clinically At start and every 6 Urea and At start
eGFR relevant months; more often electrolytes every
U&Es if there is evidence 6 months
including of deterioration of
Calcium the patient or if
they start taking
drugs such as ACE
inhibitors, diuretics
or NSAIDs
Full blood Yes If clinically A start of treatment At start and at 6 At start and at 6 At start
count relevant. months and months
Mandatory for repeat annually
clozapine
Blood (plasma) Yes Yes At start and at 12
glucose weeks; more
fasting or often if evidence
HbA1c of elevated levels
Lipid profile Yes Yes At start and at 12
weeks; more
often if elevated
levels
Mersey Care Clinical Guideline/Formulary Document Updated: Jan 2019
Bipolar Affective Disorder Next Review: Jan 2021 18Monitoring for all patients Monitoring for specific drugs
Test or Initial 6 months Annual Antipsychotics Lithium Valproate* Carbamazepine Lamotrigine
measurement health check up
check
Blood Yes Yes At start and at
pressure/ each dose
Pulse change
Prolactin Yes If symptoms of
raised prolactin
develop
ECG If indicated by If indicated At start if At start, especially
history or by history specified by if risk factors for or
clinical picture or clinical license; if there existing
picture are risk factors cardiovascular
for, history of or disease
existing cardio-
vascular disease
or if an inpatient
Weight/height Yes Yes Yes weekly for the first At start then every At start and at 6 At start and at 6
BMI 6 weeks, then at 6 months or more if months and months if the
12 weeks; more the patient gains repeat annually; patient gains
often if patient weight rapidly more often if weight rapidly
gains weight patient gains
rapidly weight rapidly
Diet Nutritional Dietary advice Dietary and fluid
Status intake advice
Physical Yes Yes At start then
Activity annually
Mersey Care Clinical Guideline/Formulary Document Updated: Jan 2019
Bipolar Affective Disorder Next Review: Jan 2021 19Monitoring for Monitoring for specific drugs
all patients
Test or Initial health Annual Antipsychotics Lithium Valproate* Carbamazepine Lamotrigine
measurement check check up
Drug screening If suggested by
and chest X-ray the history or
clinical picture
EEG, MRI, CT If organic
scans aetiology or
comorbidity is
suspected
Smoking/ Yes Yes
alcohol
Serum levels of 1 week after initiation Only if there is If clinically
drug and every 5-7 days evidence of relevant
after every dose ineffectiveness
change until levels or poor
stable, then every 3 adherence or
months for the first toxicity
year then 3-6 months
depending on risk
factors
Mersey Care Clinical Guideline/Formulary Document Updated: Jan 2019
Bipolar Affective Disorder Next Review: Jan 2021 20References 1. 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 2. 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 3. NICE QS95 (2015): Bipolar disorder in adults. http://www.nice.org.uk/guidance/qs95 4. 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 5. Royal College of Psychiatrists Position Statement 04/18. Withdrawal of, and alternatives to, valproate-containing medicines in girls and women of childbearing potential who have a psychiatric illness. December 2018. https://www.bap.org.uk/pdfs/PS04-18-December2018.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. NICE Clinical Knowledge Summaries. Bipolar disorder. Last revised in September 2017. http://cks.nice.org.uk/bipolar-disorder 10. BNF online at: https://www.medicinescomplete.com/mc/bnf/current/ 11. Martindale – The complete drug reference online at: http://www.medicinescomplete.com/mc/ [subscription required] 12. SPC for drugs referred to in this guideline can be found in the Electronic Medicines Compendium (http://emc.medicines.org.uk/). 13. Shared Care Lithium guideline – Pan Mersey Area. https://www.panmerseyapc.nhs.uk/media/2083/lithium_sharedcare.pdf Mersey Care Clinical Guideline/Formulary Document Updated: Jan 2019 Bipolar Affective Disorder Next Review: Jan 2021 21
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