Dose adjustments Manufacturer advises consider dose
reduction in severe impairment and end-stage renal
▶ Manufacturer advises to conduct a baseline evaluation to
identify patients at risk of somnolence, sedation,
hypotension, bradycardia, QT-prolongation, and
arrhythmia; this should include assessment of
cardiovascular status. Monitor for signs of these adverse
effects weekly during dose titration and then every
3 months during the first year of treatment, and every
6 months thereafter. Monitor BMI prior to treatment and
then every 3 months for the first year of treatment, and
every 6 months thereafter. More frequent monitoring is
advised following dose adjustments.
▶ Monitor blood pressure and pulse during dose downward
titration and following discontinuation of treatment.
l TREATMENT CESSATION Manufacturer advises avoid abrupt
withdrawal; consider dose tapering to minimise potential
l DIRECTIONS FOR ADMINISTRATION Manufacturer advises
avoid administration with high fat meals (may increase
l PATIENT AND CARER ADVICE Patients or carers should be
counselled on administration of guanfacine modifiedrelease tablets.
Missed doses Manufacturer advises that patients and
carers should inform their prescriber if more than one dose
is missed; consider dose re-titration.
Driving and skilled tasks Manufacturer advises patients and
carers should be counselled about the effects on driving
and performance of skilled tasks—increased risk of
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
CAUTIONARY AND ADVISORY LABELS 2, 25
▶ Intuniv (Shire Pharmaceuticals Ltd) A
Guanfacine (as Guanfacine hydrochloride) 1 mg Intuniv 1mg
modified-release tablets | 28 tablet P £56.00 DT = £56.00
Guanfacine (as Guanfacine hydrochloride) 2 mg Intuniv 2mg
modified-release tablets | 28 tablet P £58.52 DT = £58.52
Guanfacine (as Guanfacine hydrochloride) 3 mg Intuniv 3mg
modified-release tablets | 28 tablet P £65.52 DT = £65.52
Guanfacine (as Guanfacine hydrochloride) 4 mg Intuniv 4mg
modified-release tablets | 28 tablet P £76.16 DT = £76.16
3.3 Bipolar disorder and mania
Mania and hypomania 08-Jun-2018
Antimanic drugs are used to control acute attacks and to
prevent recurrence of episodes of mania or hypomania.
Long-term treatment of bipolar disorder should continue for
at least two years from the last manic episode and up to five
years if the patient has risk factors for relapse.
An antidepressant drug may also be required for the
treatment of co-existing depression, but should be avoided
in patients with rapid-cycling bipolar disorder, a recent
history of hypomania, or with rapid mood fluctuations.
Use of benzodiazepines (such as lorazepam p. 339) may be
helpful in the initial stages of treatment for behavioural
disturbance or agitation; they should not be used for long
periods because of the risk of dependence.
Antipsychotic drugs (normally olanzapine p. 398, quetiapine
p. 401, or risperidone p. 402) are useful in acute episodes of
mania and hypomania; if the response to antipsychotic drugs
is inadequate, lithium or valproate may be added. An
antipsychotic drug may be used concomitantly with lithium
or valproate in the initial treatment of severe acute mania.
See Important safety information, Conception and
contraception, and Pregnancy in the valproic acid p. 354 and
sodium valproate p. 327 monographs.
Olanzapine can be used for the long-term management of
bipolar disorder in patients whose manic episode responded
to olanzapine therapy. It can be given either as
monotherapy, or in combination with lithium or valproate if
BNF 78 Bipolar disorder and mania 353
the patient has frequent relapses or continuing functional
Asenapine p. 356, a second-generation antipsychotic, is
licensed for the treatment of moderate to severe manic
episodes associated with bipolar disorder.
When discontinuing antipsychotics, the dose should be
reduced gradually over at least 4 weeks if the patient is
continuing with other antimanic drugs; if the patient is not
continuing with other antimanic drugs or if there is a history
of manic relapse, a withdrawal period of up to 3 months
Carbamazepine p. 311 may be used under specialist
combination of other prophylactic drugs; it is used in
patients with rapid-cycling manic-depressive illness (4 or
more affective episodes per year). The dose of
carbamazepine should not normally be increased if an acute
Valproate (valproic acid (as the semisodium salt) and sodium
valproate) is used for the treatment of manic episodes
associated with bipolar disorder. It must be started and
supervised by a specialist experienced in managing bipolar
disorder. Valproate (valproic acid and sodium valproate) is
also used for the prophylaxis of bipolar disorder. Because of
its high teratogenic risk, valproate must not be used in
females of childbearing potential unless the conditions of
the Pregnancy Prevention Programme are met and
alternative treatments are ineffective or not tolerated.
Valproic acid and sodium valproate must not be used during
pregnancy in bipolar disorder. The benefit and risk of
valproate therapy should be carefully reconsidered at regular
treatment reviews. For further information, see Important
safety information, Conception and contraception, and
Pregnancy in the valproic acid and sodium valproate
In patients with frequent relapse or continuing functional
impairment, consider switching therapy to lithium or
olanzapine, or adding lithium or olanzapine to valproate. If a
patient taking valproate experiences an acute episode of
mania that is not ameliorated by increasing the valproate
dose, consider concomitant therapy with olanzapine,
Lithium salts are used in the prophylaxis and treatment of
mania, hypomania and depression in bipolar disorder
(manic-depressive disorder), and in the prophylaxis and
treatment of recurrent unipolar depression. Lithium is also
used as concomitant therapy with antidepressant medication
in patients who have had an incomplete response to
treatment for acute bipolar depression and to augment other
antidepressants in patients with treatment-resistant
depression [unlicensed indication]. It is also licensed for the
treatment of aggressive or self-harming behaviour.
The decision to give prophylactic lithium requires
specialist advice, and must be based on careful consideration
of the likelihood of recurrence in the individual patient, and
the benefit of treatment weighed against the risks. The full
prophylactic effect of lithium may not occur for six to twelve
months after the initiation of therapy. Olanzapine or
valproate (given alone or as adjunctive therapy with lithium)
are alternative prophylactic treatments in patients who
experience frequent relapses or continued functional
Other drugs used for Bipolar disorder and mania
p. 400 . Prochlorperazine, p. 389 . Zuclopenthixol acetate,
Treatment of manic episodes associated with bipolar
▶ Adult: Initially 750 mg daily in 2–3 divided doses, then
increased to 1–2 g daily, adjusted according to
response, doses greater than 45 mg/kg daily require
▶ Adult: Initially 250 mg twice daily, then increased if
necessary to 1 g daily in divided doses
DOSE EQUIVALENCE AND CONVERSION
▶ Semisodium valproate comprises equimolar amounts
of sodium valproate and valproic acid.
▶ Adult: Initially 600 mg daily in 2–4 divided doses,
increased in steps of 150–300 mg every 3 days; usual
maintenance 1–2 g daily in 2–4 divided doses, max.
2.5 g daily in 2–4 divided doses
DOSE EQUIVALENCE AND CONVERSION
▶ Convulex ® has a 1:1 dose relationship with products
containing sodium valproate, but nevertheless care is
needed if switching or making changes.
l UNLICENSED USE Not licensed for migraine prophylaxis.
MHRA/CHM ADVICE: VALPROATE MEDICINES: CONTRA-INDICATED
IN WOMEN AND GIRLS OF CHILDBEARING POTENTIAL UNLESS
CONDITIONS OF PREGNANCY PREVENTION PROGRAMME ARE MET
Valproate is highly teratogenic and evidence supports
that use in pregnancy leads to neurodevelopmental
disorders (approx. 30–40% risk) and congenital
malformations (approx. 10% risk).
Valproate must not be used in women and girls of
childbearing potential unless the conditions of the
Pregnancy Prevention Programme are met (see
Conception and contraception) and only if other
treatments are ineffective or not tolerated, as judged by
Use of valproate in pregnancy is contra-indicated for
migraine prophylaxis [unlicensed] and bipolar disorder;
it must only be considered for epilepsy if there is no
suitable alternative treatment (see Pregnancy).
Women and girls (and their carers) must be fully
informed of the risks and the need to avoid exposure to
valproate medicines in pregnancy; supporting materials
have been provided to use in the implementation of the
Pregnancy Prevention Programme (see Prescribing and
dispensing information). The MHRA advises that:
. GPs must recall all women and girls who may be of
childbearing potential, provide the Patient Guide,
check they have been reviewed by a specialist in the
last year and are on highly effective contraception;
. Specialists must book in review appointments at least
annually with women and girls under the Pregnancy
Prevention Programme, re-evaluate treatment as
354 Mental health disorders BNF 78
necessary, explain clearly the conditions as outlined in
the supporting materials and complete and sign the
Risk Acknowledgement Form—copies of the form must
be given to the patient or carer and sent to their GP;
. Pharmacists must ensure valproate medicines are
dispensed in whole packs whenever possible—all packs
dispensed to women and girls of childbearing potential
should have a warning label either on the carton or via
a sticker. They must also discuss risks in pregnancy
with female patients each time valproate medicines
are dispensed, ensure they have the Patient Guide and
have seen their GP or specialist to discuss their
treatment and the need for contraception.
MHRA/CHM ADVICE: VALPROATE MEDICINES: ARE YOU ACTING IN
COMPLIANCE WITH THE PREGNANCY PREVENTION MEASURES?
The MHRA advises that all healthcare professionals must
continue to identify and review all female patients on
valproate, including when used outside licensed
indications (off-label use) and provide them with the
patient information materials every time they attend
appointments or receive their medicines.
Guidance for psychiatrists on the withdrawal of, and
alternatives to, valproate in women of child-bearing
potential who have a psychiatric illness is available from
the Royal College of Psychiatrists.
MHRA/CHM ADVICE: VALPROATE MEDICINES AND SERIOUS
HARMS IN PREGNANCY: NEW ANNUAL RISK ACKNOWLEDGEMENT
FORM AND CLINICAL GUIDANCE FROM PROFESSIONAL BODIES TO
SUPPORT COMPLIANCE WITH THE PREGNANCY PREVENTION
The Annual Risk Acknowledgement Form has been
updated and should be used for all future reviews of
female patients on valproate. Specialists should comply
with guidance given on the form if they consider the
patient is not at risk of pregnancy, including the need for
review in case her risk status changes.
Guidance has been published to support healthcare
professionals with the use of valproate. These include a
summary by NICE of their guidance and safety advice,
pan-college guidance by national healthcare bodies, and
paediatric guidance by the British Paediatric Neurology
Association and the Royal College of Paediatrics and
l CONTRA-INDICATIONS Acute porphyrias p. 1058 . known
or suspected mitochondrial disorders (higher rate of acute
liver failure and liver-related deaths). personal or family
history of severe hepatic dysfunction
l CAUTIONS Systemic lupus erythematosus
▶ Liver toxicity Liver dysfunction (including fatal hepatic
failure) has occurred in association with valproate
(especially in children under 3 years and in those with
metabolic or degenerative disorders, organic brain disease
or severe seizure disorders associated with mental
retardation) usually in first 6 months and usually involving
multiple antiepileptic therapy. Raised liver enzymes
during valproate treatment are usually transient but
patients should be reassessed clinically and liver function
(including prothrombin time) monitored until return to
normal—discontinue if abnormally prolonged
prothrombin time (particularly in association with other
Consider vitamin D supplementation in patients who are
immobilised for long periods or who have inadequate sun
exposure or dietary intake of calcium.
l INTERACTIONS → Appendix 1: antiepileptics
diarrhoea . drowsiness . encephalopathy . fine postural
SIDE-EFFECTS, FURTHER INFORMATION Hepatic
dysfunction Withdraw treatment immediately if
persistent vomiting and abdominal pain, anorexia,
jaundice, oedema, malaise, drowsiness, or loss of seizure
Pancreatitis Discontinue treatment if symptoms of
l CONCEPTION AND CONTRACEPTION The MHRA advises
that all women and girls of childbearing potential being
treated with valproate medicines must be supported on a
Pregnancy Prevention Programme—pregnancy should be
excluded before treatment initiation and highly effective
contraception must be used during treatment.
l PREGNANCY For migraine prophylaxis[unlicensed] and
bipolar disorder, the MHRA advises that valproate must not
be used. For epilepsy, the MHRA advises valproate must
not be used unless there is no suitable alternative
treatment; in such cases, access to counselling about the
risks should be provided (see Healthcare Professional
Guide for more information) and a Risk Acknowledgement
Form signed by both specialist and patient. If valproate is
to be used during pregnancy, the lowest effective dose
should be prescribed in divided doses to avoid peaks in
plasma-valproate concentrations; doses greater than 1 g
daily are associated with an increased risk of
teratogenicity. Neonatal bleeding (related to
hypofibrinaemia). Neonatal hepatotoxicity also reported.
See also Pregnancy in Epilepsy p. 305.
Monitoring Specialist prenatal monitoring should be
instigated when valproate has been taken in pregnancy.
The dose should be monitored carefully during
pregnancy and after birth, and adjustments made on a
l BREAST FEEDING Present in milk—risk of haematological
disorders in breast-fed newborns and infants.
l HEPATIC IMPAIRMENT Manufacturer advises avoid.
▶ Monitor closely if dose greater than 45 mg/kg daily.
▶ Monitor liver function before therapy and during first
6 months especially in patients most at risk.
▶ Measure full blood count and ensure no undue potential
for bleeding before starting and before surgery.
l EFFECT ON LABORATORY TESTS False-positive urine tests
l TREATMENT CESSATION g In bipolar disorder, avoid
abrupt withdrawal; if treatment with valproate is stopped,
reduce the dose gradually over at least 4 weeks. h
l PRESCRIBING AND DISPENSING INFORMATION The
Pregnancy Prevention Programme is supported by the
following materials provided by the manufacturer: Patient
Guide, Guide for Healthcare Professionals, Risk
Acknowledgement Form, and for pharmacists, Patient Cards
and Stickers with warning symbols; the MHRA has also
produced a patient information sheet providing advice for
women and girls taking valproate medicines.
CONVULEX ® Patients being treated for epilepsy may need
to be maintained on a specific manufacturer’s branded or
generic oral valproic acid product.
BNF 78 Bipolar disorder and mania 355
Valproate use by women and girls The MHRA advises women
and girls should not stop taking valproate without first
discussing it with their doctor.
Blood or hepatic disorders Patients or their carers should be
told how to recognise signs and symptoms of blood or liver
disorders and advised to seek immediate medical attention
Pancreatitis Patients or their carers should be told how to
recognise signs and symptoms of pancreatitis and advised
to seek immediate medical attention if symptoms such as
abdominal pain, nausea, or vomiting develop.
Pregnancy Prevention Programme Pharmacists must ensure
that female patients have a patient card—see also
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug. Forms available
from special-order manufacturers include: oral suspension, oral
CAUTIONARY AND ADVISORY LABELS 8, 10, 21, 25
Valproic acid 150 mg Convulex 150mg gastro-resistant capsules |
100 capsule P £3.68 DT = £3.68
Valproic acid 300 mg Convulex 300mg gastro-resistant capsules | 100 capsule P £7.35 DT = £7.35
Valproic acid 500 mg Convulex 500mg gastro-resistant capsules | 100 capsule P £12.25 DT = £12.25
CAUTIONARY AND ADVISORY LABELS 10, 21, 25
Valproic acid (as Valproate semisodium) 250 mg Depakote 250mg
gastro-resistant tablets | 30 tablet P £5.69 | 90 tablet P £17.08 DT = £17.08
Valproic acid (as Valproate semisodium) 500 mg Depakote 500mg
gastro-resistant tablets | 30 tablet P £11.37 | 90 tablet P £34.11 DT = £34.11
ANTIPSYCHOTICS › SECONDGENERATION
Monotherapy for the treatment of moderate to severe
manic episodes associated with bipolar disorder
▶ Adult: Initially 10 mg twice daily, reduced to 5 mg twice
daily, adjusted according to response
Combination therapy for the treatment of moderate to
severe manic episodes associated with bipolar disorder
▶ Adult: Initially 5 mg twice daily, increased if necessary
to 10 mg twice daily, adjusted according to response
l CAUTIONS Dementia with Lewy Bodies
l INTERACTIONS → Appendix 1: asenapine
▶ Rare or very rare Accommodation disorder. rhabdomyolysis
l PREGNANCY Use only if potential benefit outweighs risk—
l BREAST FEEDING Avoid—no information available.
l HEPATIC IMPAIRMENT Manufacturer advises caution in
moderate impairment; avoid in severe impairment (risk of
l RENAL IMPAIRMENT Use with caution if eGFR less than
l PATIENT AND CARER ADVICE Patient or carer should be
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