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Mood Stabilisers Guidelines
MOOD STABILISERS
GUIDELINES
TREATMENT OF BIPOLAR
AFFECTIVE DISORDER
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Mood Stabilisers Guidelines
Authors:
Ms Diane Booth, Chief Pharmacist, Berkshire Healthcare NHS Foundation
Trust.
Mrs Kiran Hewitt, Lead Clinical Pharmacist, Berkshire Healthcare NHS
Foundation Trust.
Mrs Katie Sims, Clinical Pharmacist, Berkshire Healthcare NHS Foundation
Trust.
Acknowledgements:
The authors would like to thank the members of the pharmacy department,
Prospect Park Hospital and the Drugs & Therapeutics Committee
representatives of Berkshire Healthcare NHS Foundation Trust who provided
help, advice and constructive feed back during the compilation of these
guidelines.
Any enquiries regarding these guidelines or other medication related
queries should be forwarded to the MIS (Medicines Information Service),
pharmacy department, Prospect Park Hospital, on 0118 960 5075/5059,
or your ward/locality pharmacist.
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Mood Stabilisers Guidelines
CONTENTS
MOOD STABILISERS GUIDELINES
TREATMENT OF BIPOLAR AFFECTIVE DISORDER
Lithium
Indications
General Treatment Principles
Formulations
Dosing
Blood Monitoring Requirements
Side Effects
Toxicity
Interactions
Valproate
Indications (licensed and unlicensed)
General Treatment Principles
Dosing & monitoring requirements
Side Effects
Carbamazepine
Indications (licensed and unlicensed)
General Treatment Principles
Dosing & monitoring requirements
Side Effects
Interactions
Lamotrigine
Antipsychotics
Treatment of a Manic Episode
Bipolar Depression
Treatment options
Rapid Cycling
Drugs used in Bipolar Disorder – Spectrum of Efficacy
Women of child bearing age
Appendix one:
NTIS guideline for the use of lithium in pregnancy
References
4
4
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4
5
5
6
6
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8
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11
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31
32
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Mood Stabilisers Guidelines
LITHIUM
Lithium is widely used in the treatment and prevention of bipolar illness, where
it may have particular efficacy in lowering the suicide rate.1
Licensed Indications:
Treatment of hypomania and mania
Prevention of recurrent affective episodes in bipolar illness and unipolar
recurrent depression
Augmentation of antidepressants for unipolar or bipolar depression
Treatment of aggression or self-harm, particularly in learning disability
General Treatment Principles
•
•
•
•
Response may take 1-3 weeks to achieve.2
“Classic” mania may respond best, particularly with a previous pattern of
illness characterised by mania followed by depression followed by a
euthymic interval, rather than depression followed by mania, or a rapidcycling illness.
Abrupt discontinuation of lithium is associated with very high relapse rates
(50% within the next 12 weeks).3 Lithium should always be tapered over at
least 4 weeks, preferably over three months.33
Use for less than 2 years has been associated with higher relapse rates
and generally should not be started unless there is a clear intention to
continue it for at least 3 years.4
Lithium Formulations
Ideally, patients should receive the same preparation of lithium each time a
prescription is dispensed. The two most commonly used brands, Priadel™
and Camcolit™, however, are extremely similar.2
Particular care should be taken when prescribing lithium liquid. This is
available as lithium citrate liquid (Li-liquid) in two strengths, equivalent to the
200mg and 400mg strengths of lithium carbonate. Prescriptions should state
the strength of the liquid prescribed as well as the dose. The frequency for the
liquid preparation is TWICE DAILY, whereas the tablets are given once-daily.
Lithium citrate 509mg/5ml = lithium carbonate 200mg (5.4mmol Li)
Lithium citrate 1.018g/5ml = lithium carbonate 400mg (10.8mmol Li)
Dosing
• Lithium tablets should be given as a once-daily dose at night.
• Lithium liquid is given TWICE daily.
• A starting dose of 400mg daily will be appropriate for most patients.
However, this should be LOWER in the elderly, in renal impairment or if
interacting drugs are already being taken. This dose should then be
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Mood Stabilisers Guidelines
adjusted according to the lithium level – see table.
Blood Monitoring Requirements
NB: A joint decision should be made between the consultant psychiatrist and GP as
to who will be responsible for these.
Before prescribing: (responsibility of who ever initiates treatment)
• Check renal, cardiac and thyroid function.
• Full blood count, ECG if there are risk factors or existing cardiovascular
disease33
• Check medical history, physical examination and weight.
• Women of child-bearing age should be advised to use reliable
contraception, and pregnancy excluded, if appropriate.
Patients should be informed about symptoms of toxicity, and the
importance of maintaining an adequate fluid balance.
During treatment establishment: (the responsibility of who ever is prescribing for the
patient at this stage)
•
•
Blood levels should be taken 12 hours after a dose
The serum level should be checked after 5-7 days, then WEEKLY until
the desired level has been achieved. Once stable, it should be checked
3-6 monthly. The “optimal” maintenance level is the highest dose
tolerated without significant side-effects. It will vary from patient to
patient.
Generally, levels of 0.6-1.0mmol/l should be aimed for.5,33 In some
individuals e.g. in acute mania, slightly higher levels may be beneficial,
although clinical vigilance is required for adverse effects5 (liaise with
consultant).
Please note that GMS contract ranges and individual lab ranges may
differ to this.
Once Stable, monitor: (the responsibility of who ever is prescribing for the patient at this
stage)
•
•
•
•
Thyroid function – 6-monthly
U&Es – 6-monthly
Lithium levels – minimum 3-monthly
Weight at six months and if the patient gains weight rapidly33
But if risk factors exist, e.g. renal disease, interacting drugs (especially
diuretics, ACE inhibitors and NSAIDs), recently changed dose, concomitant
diarrhoea and/or vomiting and hot weather, suggest monthly plasma lithium
level monitoring.
Side-effects
CNS: fatigue, dizziness, tremor, cognitive blunting, impaired coordination
GI: diarrhoea, nausea, vomiting, metallic taste, weight gain
Renal: polyuria, polydipsia, reduced glomerular filtration rate, distal tubular
function changes, diabetes insipidus
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Cardiac: ECG changes/arrhythmias
Skin: acne, rash, pruritis, psoriasis exacerbation
Other: leucocytosis, hair loss, oedema, muscular weakness, sexual
dysfunction, hypothyroidism, hyperparathyroidism,
Many common side-effects can be managed by lowering the lithium dose
Contact the MIS for patient specific advice.
Toxicity
Most patients experience toxic effects with levels above 1.5mmol/l. Levels
above 2.0mmol/l are associated with life-threatening side-effects and require
urgent treatment: haemodialysis may be needed to minimise toxicity.
Lithium toxicity should be suspected at “therapeutic” levels in compromised
patients with relevant symptoms.
Symptoms of Lithium Toxicity
Mild
nausea
diarrhoea
severe fine tremor
poor concentration
Moderate
vomiting
cerebellar ataxia
slurred speech
coarse tremor
disorientation
drowsiness
Severe
vomiting
incontinence
choreiform/parkinsonian
movement
general muscle
twitching (myoclonus)
cerebellar dysfunction
spasticity
EEG abnormalities and
seizures
apathy
coma
th
(from “Use of drugs in Psychiatry” 5 edition,
Cookson/Katona/Taylor)
Interactions
Due to lithium’s narrow therapeutic index, interactions can be important.
Some commonly encountered ones include:
(1) Diuretics – which can INCREASE lithium levels, by reducing its
clearance. Thiazides are the most hazardous, with loop diuretics being
somewhat safer.
(2) Non-steroidal anti-inflammatory drugs (NSAIDs) can INCREASE
lithium levels by up to 40%,6 although the mechanism for this is
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Mood Stabilisers Guidelines
unclear. However, it can be particularly important if a NSAID is
prescribed on a “prn” basis.
(3) ACE inhibitors can INCREASE lithium levels, by reducing its excretion.
As they can also be renally toxic, extra care is required in monitoring
renal function with this combination. Care is also needed with the
newer angiotensin 2 antagonists.
(4) Carbamazepine/haloperidol. Despite previous concerns over
neurotoxicity, these drugs can be prescribed with lithium; the chance of
a toxic reaction is minimal. Previous cases were in patients with preexisting brain damage, or using high doses of lithium and haloperidol.
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VALPROATE
(as sodium valproate “Epilim™” or valproate semisodium “Depakote™”)
epilepsy (Epilim™, EpisentaTM granules)
treatment of mania (Depakote™)
Unlicensed: prophylaxis of bipolar disorder (Epilim™ or
Depakote™))
Indications - Licensed:
Semi-sodium valproate (Depakote™) and sodium valproate (Epilim™) are
metabolised to valproic acid, which is responsible for the pharmacological
activity of both preparations. Despite small differences in bioavailability and
peak plasma levels, there are no significant differences between the two
drugs (1.00g of semi-sodium valproate is equivalent to 1.08g of sodium
valproate, this difference is not considered clinically significant). Depakote™
is only licensed for the acute treatment of mania, whilst Epilim™ and
EpisentaTM is not licensed for the treatment of bipolar illness at all in the UK.
Berkshire Healthcare NHS Foundation Trust’s recommendations are:
a) to use sodium valproate (Epilim™) for prophylaxis and treatment
b) to switch patients on Depakote to Epilim as soon as possible after
stabilisation and on discharge.
c) where possible, to use the long-acting Epilim Chrono™ preparation. This
can be given once-daily and is better tolerated. It is available in 200mg,
300mg and 500mg tablet strengths.
d) If needed use EpisentaTM prolonged release granules in patients who are
unable to swallow Epilim ChronoTM
General Treatment Principles
•
•
•
•
•
Effective for treating mania, with around a 50% response rate.7
Some evidence suggesting effectiveness for patients with depressive
symptoms at baseline.8
Effective in rapid cycling, alone or when added to lithium or
carbamazepine, even when these therapies have been ineffective 9,10
Probably as effective as lithium for prophylaxis.11
Do not prescribe routinely for women of child bearing potential. If there is
no alternative, ensure the woman is using adequate contraception, and
explain risks. 33 Valproate may cause polycystic ovaries and
hyperandrogenism in women.
Dosing and Monitoring Requirements
NB: A joint decision should be made between the consultant psychiatrist and GP as to who
will be responsible for these.
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Before treatment, monitor: (the responsibility of who ever initiates treatment)
•
Electrolytes, Liver Function Tests, Full Blood Count, weight and
height
Starting Treatment: (the responsibility of who ever is prescribing for the patient at this
stage)
•
•
•
For Epilim Chrono™ – 500mg CR daily.
For Depakote™ – 750mg as a ‘tds’ or ‘bd’ dose.
Aim for a dose of between 1000mg and 2000mg for mania, as soon as
clinically possible.
Routine Testing: (the responsibility of who ever is prescribing for the patient at this
stage)
•
•
•
•
Liver Function Tests – e.g. 6-monthly33 – more often if problems found
at baseline *see LFTs below
Full Blood Count – e.g. 6-monthly – more often if problems found at
baseline
Serum valproate level – only if indicated e.g. lack of response, drug
interaction
(aim for 50-100mg/l as trough levels; plasma levels are of limited value,
although a dose of 1000mg/day and a serum level of at least 50mg/l is
associated with response12
Common Side Effects
nausea
vomiting
mild sedation
hair loss
moderate weight gain
ataxia
tremor
.
Liver Problems:
Very rarely, valproate may cause fulminant hepatic failure, although cases
tend to be in children receiving multiple anticonvulsants and with family
histories of hepatic problems.
* Raised liver enzymes occur commonly at the start of treatment and tend to
be transient and isolated. However, patients should be evaluated and other
indicators of hepatic function monitored until they return to normal e.g.
albumin, prothrombin time. Abnormally prolonged prothrombin time could
require discontinuation of treatment.
Valproate is also associated with thrombocytopenia, leucopenia, red cell
hypoplasia and pancreatitis. Patients should be made aware of these side
effects, how to recognise the signs of blood or liver disorders and the need to
seek medical attention if they develop.
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Most side-effects of valproate are dose-related, increasing in frequency and
intensity when the level is over 100mg/l.
Use of the long-acting version, Epilim Chrono™ as a once-daily dose may be
better tolerated.
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Mood Stabilisers Guidelines
CARBAMAZEPINE
Licensed Indications
Prophylaxis of bipolar illness in patients unresponsive to lithium
Epilepsy
Trigeminal neuralgia – treatment of paroxysmal pain
General Treatment Principles
•
•
•
•
May be effective in acute mania as monotherapy, with a response rate of
around 60%.13,14,15
May be effective in bipolar depression as monotherapy.16
Perceived to be more effective than lithium in rapid-cycling illness,
although studies are contradictory.
Response is likely to occur from around 5 days to a month after initiation of
treatment.
Dosing and Monitoring Requirements
NB: A joint decision should be made between the consultant psychiatrist and GP as to who
will be responsible for these.
Before Prescribing, Monitor: (the responsibility of who ever initiates treatment)
•
Full Blood Count, Electrolytes, Liver Function Tests, Renal Function
Test, weight and height
Starting Treatment: (the responsibility of who ever is prescribing for the patient at this
stage)
•
Dosage should be titrated slowly from 200mg once or twice daily until
either the patient responds or is unable to tolerate further increases.
Doses of at least 600mg/day seem to be required in affective illness.12
Routine Testing: (the responsibility of who ever is prescribing for the patient at this
stage)
Full Blood Count – e.g. Every six months33.
Liver Function Tests – e.g. every six months 33
Weight and height – e.g. Every six months33.
Electrolytes – check sodium if symptoms of syndrome of inappropriate
ADH secretion (SIADH) occur e.g. confusion, seizures, oedema,
anorexia, nausea, muscle weakness, hypertension, cardiac failure
Carbamazepine levels:
• Carbamazepine blood levels do not appear to correlate with response,
although levels less than 7mg/l are associated with a lack of
response.12 A level may be useful to identify non-compliance, toxicity
or inadequate dosing. NICE is alone in recommending routine testing
every six months.33
• Blood samples for levels should be taken before the first dose of the
•
•
•
•
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Mood Stabilisers Guidelines
•
day (trough level).
Carbamazepine is a hepatic enzyme inducer, and will induce its own
metabolism, reducing its initial half-life as dosing continues. Hence
levels should be taken 2-4 weeks after initiation/dose increases.
Side Effects
Dizziness, drowsiness, ataxia, nausea, headache, diplopia, blurred vision
A chronic low WBC count can occur, and is usually benign. Carbamazepine
should be discontinued if the leucopenia is severe, progressive, or
accompanied by clinical manifestations e.g. sore throat, fever. One in 20,000
develops agranulocytosis and/or aplastic anaemia. Thrombocytopenia and
eosinophilia are also common.
Raised ALP and GGT can be a sign of hypersensitivity, which can lead to a
multi-organ reaction presenting as skin reactions, low WBC count, raised ALP
and GGT, and can lead to hepatitis. Treatment should be discontinued.
However, a raised GGT of up to twice normal in isolation is common and
should not cause concern – probably a result of hepatic enzyme induction.
Around 3% of patients develop a generalised erythematous rash. Mild skin
reactions are mostly transient and not hazardous and usually disappear, often
with continued treatment. However close observation is necessary and
Carbamazepine withdrawn if the rash rapidly worsens or there are
accompanying symptoms. Serious dermatological reactions can occur rarely,
e.g. toxic epidermal necrolysis.
Oedema, fluid retention, weight increase, hyponatraemia and reduced plasma
osmolality due to an ADH-like effect are common. Rarely, this can lead to
water intoxication accompanied by lethargy, confusion, headache, vomiting
and neurological abnormalities.
Interactions
Carbamazepine is a potent inducer of hepatic cytochrome P450 enzymes and
is metabolised by CYP3A4.
Carbamazepine lowers the level of antidepressants
antipsychotics
benzodiazepines
anticonvulsants
cholinesterase inhibitors
oral contraceptives - levels of steroid hormones in oral contraceptives will be
reduced, leading to possible contraceptive failure. Pills containing at least
50mcg oestradiol need to be used. Please contact pharmacy for advice on
which combinations of pills to use and the regimen recommended.
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Drugs that raise carbamazepine levels (via CYP3A4 inhibition) cimetidine
dextropropoxyphene (in co-proxamol),
verapamil,
diltiazem,
SSRIs,
erythromycin.
LAMOTRIGINE
There are too few data to recommend lamotrigine as first or second-line
therapy in bipolar affective disorder. It is unlicensed for this indication in the
UK. However, a growing body of evidence has demonstrated efficacy in
specific areas, hence use may be justified in the following areas:
•
•
•
maintenance therapy for patients with bipolar 1 disorder who have had a
recent depressive or manic episode,17,18 or history of depressive
episodes (it is licensed in the USA for this purpose). Recommended
monotherapy dosage is 25mg/day, gradually increased to 200mg/day
over 6 weeks. No additional efficacy has been demonstrated in trials
evaluating higher dosages up to 400mg/day.
acute treatment of bipolar depression at a dose of 200mg/day.19
rapid-cycling20 - increasingly seen as an early-use option for this
condition. Doses in responders were around 150mg/day.
Side-effects
Rash occurs in up to 10% of patients, usually within the first 8 weeks. It is
thought to be related to high initial lamotrigine serum levels, hence the need
for slow dose titration. Risk factors include use in children, high starting
doses, concomitant valproate therapy and previous drug allergies. The
majority of rashes are mild and self-limiting; however serious ones including
Stevens Johnson Syndrome have been reported. As it is difficult to distinguish
between a serious and more benign rash at their onset, lamotrigine should be
discontinued. If the rash is trivial and disappears, lamotrigine can be tapered
in even more slowly. If accompanied by fever, sore throat, mucosal
involvement or is diffuse and widespread, all possible provoking agents
should be stopped and reintroduction should be extremely cautious if
attempted at all.
Other side-effects include
flu-like symptoms
headache
tiredness
nausea
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dizziness
drowsiness
insomnia
diplopia
Interaction with risperidone
Significant changes in patients risperidone levels (in one case a quadrupling)
have been seen when lamotrigine is introduced or the lamotrigine dose is
altered. It would therefore seem prudent to monitor patients for an increase in
adverse effects, or a lack of therapeutic effect in patient on this combination.
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Mood Stabilisers Guidelines
Antipsychotics
Key Points
•
Moderate or severe mania is usually most rapidly controlled by
antipsychotic drugs, which have an anti-manic as well as a sedative
action. Antipsychotics are also useful in psychotic depression.21
Combining an antipsychotic agent with an antidepressant may also help
to prevent a switch to mania.
•
Atypical antipsychotics have an increasingly important role in treating
acute mania with the advantage of achieving their action without inducing
EPSE22. Response rates are further enhanced when used in
combination with mood stabilisers.23 Currently, olanzapine, risperidone
and quetiapine are licensed for treating acute mania, with olanzapine
also having a license for maintenance in bipolar disorder.
•
Among the typical antipsychotics, haloperidol is often cited as the
antipsychotic of choice. There is little good evidence to guide the choice
of dose, but increasing it above 30mg/day is not justified. However,
extrapyramidal side-effects, especially tardive dyskinesia, are a particular
concern in bipolar patients. If further sedation is needed, additional
treatment with a benzodiazepine is more appropriate, and safer.
•
Antipsychotics are often used as long term treatment; however their
place is poorly established because of the lack of evidence. They may be
appropriate for long term use, especially where psychotic features are
prominent.
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Mood Stabilisers Guidelines
Treatment of a Manic Episode5, 33
•
Antidepressants should be tapered and discontinued. The speed of this
tapering and discontinuation depends on the risk of
discontinuation/withdrawal symptoms and clinical need. Please
contact Medicines Information on 0118 960 5075 for advice.
For patients already on prophylaxis:
•
If the current episode is due to inadequate symptom control, ensure that
the highest tolerated dose is offered. For lithium, check serum levels are
within the therapeutic range; consider establishing a higher serum level
within the therapeutic range (aim for 0.8-1.0mmol/L for this acute period).
•
Initiate an antipsychotic or valproate (see flow diagram below)
•
If the current episode is due to poor adherence, establish whether this is
due to problems with side-effects, and if so, consider changing to a better
tolerated regimen.
For patients not already on prophylaxis:
•
Initiate an antipsychotic or valproate due to their rapid antimanic effect.
Atypicals should be considered due to their more favourable short-term
adverse effect profile. Lithium or carbamazepine may be considered as
short term treatments for less manic patients
In general:
•
Add benzodiazepines such as clonazepam (unlicensed) or lorazepam if
needed
•
Combine mood stabiliser (e.g. lithium or valproate) with an antipsychotic, if
necessary.
•
Parenteral antipsychotics and benzodiazepines, if needed, should be used
in line with the trust’s rapid tranquillisation policy. Do not escalate the dose
of antipsychotic to produce a sedative effect.
•
For treatment refractory patients, combinations of mood stabilisers, ECT or
clozapine can be considered – pharmacy can advise.
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Mood Stabilisers Guidelines
Stop antidepressant (if taking) – abruptly
or gradually, depending on clinical need
and risk of discontinuation/ withdrawal
symptoms
Is patient already taking antimanic
medication?
No
Yes
Consider, taking into account side effects and future
prophylaxis:
• An antipsychotic (normally olanzapine, quetiapine
or risperidone), especially if symptoms are severe
or behaviour disturbed
• Valproate if symptoms have responded before (but
avoid in women of childbearing potential)
• Lithium if symptoms have responded before, and
are not severe
If taking an antipsychotic, check the dose and
increase if necessary. If the response is inadequate,
consider adding lithium or valproate
If giving antipsychotics:
• Consider individual risk of side effects (such as
diabetes)
• Start at low doses and titrate according to response
• Consider adding valproate or lithium if response is
inadequate
• Be aware that older people are at higher risk of
sudden onset of depression after recovery from
mania
If taking valproate, increase the dose until:
• Symptoms start to improve or
• Side effects limit dose increases
If there is no improvement, consider adding
olanzapine, quetiapine, or risperidone. Monitor
carefully if the valproate dose is higher than 45mg
per kg
Consider adding short-term benzodiazepine (such as
lorazepam) for behavioural disturbance or agitation
Carbamazepine should not be routinely used for acute
mania
If taking lithium, check plasma levels:
• If below 0.8mmol/L, increase dose to a
maximum blood level of 1.0mmol/L
• If the response is not adequate, consider
adding an antipsychotic
If taking lithium or valproate and mania is
severe, consider adding an antipsychotic while
gradually increasing the dose of the original drug
If taking carbamazepine, do not routinely increase
the dose. Consider adding an antipsychotic. Drug
interactions are common with carbamazepine –
adjust doses as needed.
Gabapentin, lamotrigine and topiramate are not
recommended for acute mania
Advise all patients on:
Avoiding excessive stimulation
Calming activities
Delaying important decisions
A structured routine with lower activity level
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Mood Stabilisers Guidelines
Bipolar Depression
Guidelines for treating bipolar depression vary considerably from country to
country, and may reflect the lack of data available specifically for this
condition. Bipolar depression is generally under diagnosed, or misdiagnosed
as unipolar depression, resulting in inappropriate treatment. Despite the
differences between countries, certain aspects of treatment are unlikely to be
in dispute. These include:
•
Antidepressant monotherapy is not recommended, due to the risk of
inducing mania or rapid-cycling,24, 33 and generally worsening the overall
course of the illness. If used, they should always be combined with an antimanic agent, such as lithium, valproate or an anti-psychotic.5, 33
•
The risk of a switch to mania is greater for tricyclic antidepressants and
MAOIs, compared with other antidepressants (SSRIs in particular).24, 33
•
For patients developing depression whilst already on long-term treatment,
this treatment should be optimised before other measures are taken. This
includes insuring that the patient has had an adequate dose, for an
adequate period of time. Serum levels of mood-stabilisers such as lithium
should be checked. Compliance should be investigated. Other co-morbid
conditions should be treated or looked for e.g. personality disorder.
•
Treatment options thereafter include lithium, lamotrigine, ECT, quetiapine
or olanzapine/olanzapine-fluoxetine – see table below. The latter is an
example of the general recommendation to combine an effective
antidepressant with an anti-manic agent. Carbamazepine and valproate
have an inadequate evidence base in acute depression.5
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Mood Stabilisers Guidelines
Possible Options for Treating Bipolar Depression
Treatment
Lithium
Advantages
Overwhelming expert preference for
lithium as first-line in preference to
antidepressants, in guidelines23
Huge number of studies finding lithium
to be effective
Especially useful where a patient has
had mainly manic swings previously
Lamotrigine
ECT
Quetiapine
Olanzapine/
OlanzapineFluoxetine
combination
Small number of placebo-controlled
trials demonstrate efficacy.17,18,19,25
Well tolerated.
May be especially useful for patients
with mostly depressive swings
Of particular use for bipolar patients
who are
•
psychotic
•
treatment resistant
• high suicide risk
• pregnant 5, 26
Evidence of some benefit (possibly
greater than that from olanzapine) from
trials in both bipolar I and bipolar II
depression47,48
Evidence from recent randomised,
placebo-controlled trial28
Disadvantages
Actual evidence for efficacy of
lithium in bipolar depression is
disappointing – many trials were
poorly designed crossover trials5
Abrupt discontinuation may make
symptoms worse than no
treatment at all23
Potentially toxic – plasma
monitoring essential
May be poorly tolerated
Evidence limited to only a few
trials
Requires slow titration of drug
Optimum dose unclear
Trials exclusively in bipolar
patients do not exist although
trials in severe depression will
have included bipolar cases27
Unfavourable media portrayal
Necessitates general anaesthetic
Takes about 2-3 weeks to
differentiate from placebo47,48
Evidence from one trial only,
which was for 8 weeks only, and
not independent
No double-blind evidence yet for
maintenance treatment, although
open-label data available23
No indication generally to use
antipsychotics to treat bipolar
depression as monotherapy
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Rapid Cycling
Rapid-cycling is a sub-class of bipolar affective disorder, with four or more
affective episodes in the preceding 12 months. It is associated with female
gender, bipolar 2 disorder, current hypothyroidism and a poor response to
lithium.29 In 30–40% cases, it may be preceded by exposure to
antidepressants, and worsened by treatment with antidepressants5. It is
notoriously difficult to treat.
•
Identify and treat conditions such as hypothyroidism or substance misuse
that may contribute to cycling
•
Taper and discontinue any possible causative antidepressants
•
For initial treatment, consider lithium, valproate or lamotrigine. Although
sometimes ineffective as monotherapy, a synergistic effect has been
shown in combination with carbamazepine.30
•
If ineffective, consider combining two or more mood stabilisers, even if
ineffective individually.
•
Other possible strategies include use of thyroxine to achieve supra normal
free thyroxine levels, clozapine or other atypical antipsychotics.31,32
Evidence is limited – please contact Medicines Information on 0118 960
5075 to discuss further.
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Mood Stabilisers Guidelines
Drugs used in Bipolar Disorder – Spectrum of Efficacy
Efficacy for
Notes
Acute
Acute
Mania
Depression Rapidmania depression Prophylaxis Prophylaxis Cycling
Lithium
++
++
+++
++
+/May be more
effective in
combination
with an
antipsychotic.
Valproate
+++
+/++
++
++
Contradictory
evidence for
efficacy in
bipolar
depression
Carbamazepine +/++
+/+/++
+/++
++
Generally less
effective than
lithium
Antipsychotics
+++
-/+
++
+
+
Useful for
psychotic
depression.
Olanzapine
has modest
antidepressant
effect.
Lamotrigine
++
+
++
++
Drug
Key:
+++ Evidence from meta-analysis of RCTs or multiple RCTs
++ Trial evidence, but lack of RCTs
+ Other evidence, but inadequate
- Lack of evidence/negative effect
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Mood Stabilisers Guidelines
Women of Childbearing Age
Since pregnancy appears not to be protective against recurrence of bipolar
disorder, patients must be informed about both the effects of foetal exposure
to psychotropic medication as well as the critical importance of maintaining
euthymia during pregnancy.36 No decision is risk-free and no decision is
perfect, but clinicians should work collaboratively with the patient. Women
with similar illness histories may make very different decisions regarding
treatment options36.
The baseline risk for major malformations among live births to women not
taking any mediation or other exogenous, non-food substances during
pregnancy is in the range of 2% to 4% and the risk of spontaneous abortions
is about 10-20% .34,43
From one trial the risk of relapse for bipolar women who discontinued mood
stabilisers during pregnancy was 81% compared to 21% in those taking mood
stabilisers.36
The principles for prescribing in this group are35:
• Assume that pregnancy is imminent for all female patients between the
ages of 8 and 48 years
• Document method of birth control at all visits
• Recommend folic acid for all women who are trying for a baby or who
are pregnant, 400mcg daily unless taking an antiepileptic drug when it
should be 5mg od during attempted conception and the first trimester
• Assume that women will want to breast feed
• Valproate should not be prescribed routinely for women of childbearing potential. If no effective alternative to valproate can be
identified, adequate contraception should be used, and the risks of
taking valproate during pregnancy should be explained.33
• Patients on enzyme-inducing anti-epileptic drugs (e.g. carbamazepine)
should take vitamin K 20mg daily during the last month of pregnancy
and 1mg IM should be given IM to the baby both at birth and at one
month of age.49
• Of the antiepileptics lamotrigine can be considered the preferred choice
in pregnancy49
Pregnancy
Carbamazepine: The risk of foetal malformations with carbamazepine is
2.3%.37 Epileptic women treated with carbamazepine have a 2-3 fold
increased risk of malformations, i.e. up to 10% (however this will include the
risk of both the epilepsy and the medication). 41 Carbamazepine is associated
with a 1% risk of neural tube defects. Concurrent folic acid 5mg daily up to
week 12 of pregnancy is recommended.38, 41
There is an increased risk of other types of malformations including nail
hypoplasia and other minor digital anomalies, but not specific syndrome of
defects. A decrease in head circumference has also been reported, however
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there is no evidence of adverse effects on postnatal development up to four
years of age in babies born with a reduced head circumference.41
To minimise the risks it is recommended that: folic acid 5mg daily is given up
to 12 weeks of pregnancy, a dating scan is performed at 12 weeks, an alphafeto-protein (AFP) at 16-18 weeks and a detailed ultrasound scan at around
20-22 weeks will detect approximately 50% of gross malformations e.g. neural
tube defects and cardiac anomalies.38, 41
Lamotrigine: The risk of foetal malformations with lamotrigine is 3%
(although data is still emerging).37
Teratogenic risk cannot be excluded. Inadvertent exposure is not grounds for
termination of pregnancy. The UK Epilepsy and Pregnancy Register
published data from 647 monotherapy lamotrigine cases with outcome data.
They reported 21 (3.2%) malformations which included a neural tube defect,
cleft palate, four cardiac malformations, six cases of hypospadias or
genitourinary tract defects, three gastrointestinal tract defects, two skeletal
malformations, and four other unspecified malformations. This data is
representative of the other registries and trials. To minimise the risks it is
recommended that: folic acid 5mg daily is given up to 12 weeks of pregnancy,
an expanded prenatal diagnosis with an alpha fetoprotein at week 16 of
gestation and a detailed ultrasound around week 20 should be considered.42
Lithium passes freely across the placenta. It has an association with the
cardiac malformation Ebstein’s anomaly where there is a distorted and
displaced tricuspid valve with secondary abnormalities of the right atrium and
ventricle (relative risk is 10-20 times more than control, but the absolute risk is
low at 1:1000). The overall risk of congenital heart defects is 0.9%-12% for
babies exposed to lithium in the first trimester versus 0.5-1.0% in the general
population. The period of maximum risk to the foetus is 2-6 weeks after
conception.
Although structural malformations may occur when lithium is used in the first
trimester, other types of fetal toxicity can occur during the remaining stages of
pregnancy. Transient cardiotoxicity has been reported even at term. Other
fetotoxic effects thought to be associated with maternal lithium exposure are
premature births, perinatal mortality, fetal macrosomia, lethargy, hypotonia,
feeding difficulties, goitre and transient toxicity, although more recent studies do
not always support this.
Slow discontinuation (over at least one month) before conception is preferred
if the course of the illness allows. For women who discontinue lithium before
conception the relapse rate postpartum may be as high as 70%. If
discontinuation is unsuccessful during pregnancy restart and continue. If
lithium is continued during pregnancy, high-resolution ultrasound and
echocardiography should be performed at 6 and 18 weeks of gestation. In the
third trimester, the use of lithium may be problematic because of changing
pharmacokinetics and increasing dose of lithium may be required to maintain
the lithium level during pregnancy as total body water increases, but the
requirements return abruptly to pre-pregnancy levels immediately after
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Mood Stabilisers Guidelines
delivery.37,43 See appendix one for the guideline on management of a patient
with lithium in pregnancy.44
Valproate: The teratogenic effects of valproate occurs early in gestation,
between weeks 4 and 5.36 The risk of foetal malformations with valproate is
7.2%.37
A variety of malformations have been described especially neural tube
defects,
approximately a 2% risk. Urogenital abnormalities such as hypospadias,
testicular
hypoplasia and undescended testes have been described also. There is
inconclusive evidence indicating that some babies will have a number of
anomalies known as the Valproate Syndrome (craniofacial anomalies,
epicanthal folds inferiorly, small anteverted nose, shallow philtrum, flat nasal
bridge, long upper lip, downturned mouth and a thin vermilion border).
There is also thought to be an increased risk of autism spectrum disorder
following in utero exposure to valproate, but the size of this risk is not yet
clear.39
Valproate has also been associated with an increased risk of fetal toxicity.
The suggestions for patients taking valproate who are not able to come off it
before becoming pregnant are:
• If possible reduce the peak height levels of the drug by dosing more
frequently or use a modified release preparation, but only if this does not
interfere with symptom control.
• Folic acid 5mg daily up to12 weeks of pregnancy may reduce the
incidence of neural tube defects
• A dating scan at 12 weeks
• AFP at 16-18 weeks
• A detailed ultrasound scan at around 20-22 weeks will detect
approximately 50% of gross malformations e.g. neural tube defects,
cardiac anomalies
Breast milk
The levels of exposure via breast milk are typically significantly lower than via
the placenta. Therefore if a baby has been exposed to a drug throughout
pregnancy it is illogical to change the medication for the breastfeeding
period.35
Drugs should be avoided if the infant is pre-mature, or has renal, hepatic,
cardiac or neurological impairment. Neonates (and particularly premature
neonates) are at greater risk from exposure to drugs via breast milk, because
of an immature excretory function and the consequent risk of drug
accumulation.
Carbamazepine is excreted in breast milk. Infant serum levels range from 665% of maternal serum levels. Adverse effects have been reported in a
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number of infants exposed to carbamazepine during breastfeeding. These
include one case of cholestatic hepatitis, and one of transient hepatic
dysfunctions with hyperbilirubinaemia and elevated GGT. The adverse
effects in the first case resolved after discontinuation of breast-feeding and
the second resolved despite continued feeding. Other adverse effects
reported include seizure-like activity, drowsiness, irritability and high-pitched
crying in one infant whose mother was on multiple agents, hyperexcitability in
two infants and poor feeding in another three. In contrast, in a number of
infants, no adverse effects were noted.37
The American Academy of Paediatrics describes carbamazepine as a
‘medication usually compatible with breastfeeding’. The amount of
carbamazepine transferred to the infant is apparently quite low. Although the
half-life of carbamazepine appears shorter in infants than in adults, infants
should still be monitored for sedative effects.40
Lamotrigine is excreted in breast milk. Infant serum levels range between 18
and 50% of maternal serum levels. No adverse effects have been reported in
exposed infants. However, because of the risk of life-threatening rashes, it is
advisable to avoid lamotrigine while breast-feeding until more data on its
effects become available.37
The American Academy of Paediatrics describes lamotrigine as a ‘drug whose
effect on nursing infants is unknown but may be of concern’. It is probably
advisable to monitor the infant’s plasma level closely to ensure safety.40
Lithium is excreted in breast milk. Infant serum levels range from 5% to
200% of maternal serum concentrations, but is expected to be about 30-40%
of the maternal level, most often without untoward effects in the infant.
Adverse effects have been reported in infants exposed to lithium while breastfeeding. One infant developed cyanosis, lethargy, hypothermia, hypotonia and
a heart murmur, all of which resolved within 3 days of stopping breast-feeding.
The infant was exposed to lithium in utero. Non-specific signs of toxicity have
been reported in others. There are also reports of no adverse effects in some
infants exposed to lithium while breast-feeding. Opinions on the use of lithium
while breast-feeding vary from absolute contraindication to mother’s informed
choice. Conditions which may alter the infant’s electrolyte balance and state
of hydration must be borne in mind. If it is used, the infant must be carefully
monitored for signs of toxicity. 37
The American Academy of Paediatrics describes lithium as a ‘drug associated
with significant side effects and should be given with caution’. If the infant
continues to breastfeed, it is strongly suggested that the infant be closely
monitored for serum lithium levels. Lithium does not reach steady state levels
for approximately 10 days. Clinicians may wish to wait at least this long prior
to evaluating the infant’s serum lithium level, or sooner if symptoms occur. In
addition, lithium is known to reduce thyroxine production, and periodic thyroid
evaluation should be considered. Because hydration status of the infant can
alter lithium levels dramatically, the clinician should observe changes in
hydration carefully.40
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Valproate is excreted in breast milk. Infant serum levels vary from
undetectable to 40% of maternal serum levels. Thrombocytopenia and
anaemia were reported in a 3-month-old infant exposed to valproate in utero
and while breast-feeding. This reversed on stopping breast-feeding. 37
The American Academy of Paediatrics describes valproate as a ‘usually
compatible with breastfeeding’. Breastfeeding would appear safe. However,
the infant may need monitoring for liver and platelet changes.40
NICE recommendations for the management of bipolar
disorder during pregnancy and post-natal period33, 46
General principles of management for women
No psychotropric drug is specifically licensed for use during pregnancy or
when breastfeeding.
The absolute and relative risks of problems associated with both treating and
not treating the bipolar disorder during pregnancy should be discussed with
women.
Valproate should not be prescribed routinely for women of child-bearing
potential. If no effective alternative to valproate can be identified,
adequate contraception should be used, and the risks of taking
valproate during pregnancy should be explained.
More frequent contact by specialist mental health services (including, where
appropriate, specialist perinatal mental health services), working closely with
maternity services, should be considered for pregnant women with bipolar
disorder, because of the increased risk of relapse during pregnancy and the
postnatal period.
A written plan for managing a woman’s bipolar disorder during the pregnancy,
delivery and postnatal period should be developed as soon as possible. This
should be developed with the patient and significant others, and shared with
her obstetrician, midwife, GP and health visitor. All medical decisions should
be recorded in all versions of the patient's notes. Information about her
medication should be included in the birth plan and notes for postnatal care.
If a pregnant woman with bipolar disorder is stable on an antipsychotic and
likely to relapse without medication, she should be maintained on the
antipsychotic, and monitored for weight gain and diabetes.
The following drugs should not be routinely prescribed for pregnant women
with bipolar disorder:
• valproate – because of risk to the fetus and subsequent child
development
• carbamazepine – because of its limited efficacy and risk of harm to the
fetus
• lithium – because of risk of harm to the fetus, such as cardiac problems
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• lamotrigine – because of the risk of harm to the fetus
• paroxetine – because of the risk of cardiovascular malformations in the
fetus
• long-term treatment with benzodiazepines – because of risks during
pregnancy and the immediate postnatal period, such as cleft palate and floppy
baby syndrome.
Women planning a pregnancy
Women with bipolar disorder who are considering pregnancy should normally
be advised to stop taking valproate, carbamazepine, lithium and lamotrigine,
and alternative prophylactic drugs (such as an antipsychotic) should be
considered.
Women taking antipsychotics who are planning a pregnancy should be
advised that the raised prolactin levels associated with some antipsychotics
reduce the chances of conception. If prolactin levels are raised, an alternative
drug should be considered.
If a woman who needs antimanic medication plans to become pregnant, a
low-dose typical or atypical antipsychotic should be considered, because they
are of least known risk.
If a woman taking lithium plans to become pregnant, the following options
should be considered:
• if the patient is well and not at high risk of relapse – gradually
stopping lithium
• if the patient is not well or is at high risk of relapse:
− switching gradually to an antipsychotic, or
− stopping lithium and restarting it in the second trimester if the woman
is not planning to breastfeed and her symptoms have responded better to
lithium than to other drugs in the past, or
− continuing with lithium, after full discussion of the risks, while trying to
conceive and throughout the pregnancy, if manic episodes have complicated
the woman’s previous pregnancies, and her symptoms have responded well
to lithium.
If a woman remains on lithium during pregnancy, serum lithium levels should
be monitored every 4 weeks, then weekly from the 36th week, and less than
24 hours after childbirth. The dose should be adjusted to keep serum levels
within the therapeutic range. The woman should maintain adequate fluid
intake.
If a woman planning a pregnancy becomes depressed after stopping
prophylactic medication, psychological therapy (CBT) should be offered in
preference to an antidepressant because of the risk of switching associated
with antidepressants. If an antidepressant is used, it should usually be an
SSRI (but not paroxetine because of the risk of cardiovascular malformations
in the fetus) and the woman should be monitored closely.
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Women with an unplanned pregnancy
If a woman with bipolar disorder has an unplanned pregnancy:
• the pregnancy should be confirmed as quickly as possible
• the woman should be advised to stop taking valproate,
carbamazepine and lamotrigine
• if the pregnancy is confirmed in the first trimester, and the woman is
stable, lithium should be stopped gradually over 4 weeks, and the woman
informed that this may not remove the risk of cardiac defects in the fetus
• if the woman remains on lithium during pregnancy serum lithium
levels should be checked every 4 weeks, then weekly from the 36th week,
and less than 24 hours after childbirth; the dose should be adjusted to keep
serum levels within the therapeutic range, and the woman should maintain
adequate fluid intake
• an antipsychotic should be offered as prophylactic medication
• offer appropriate screening and counselling about the continuation of
the pregnancy, the need for additional monitoring and the risks to the
fetus if the woman stays on medication.
If a woman with bipolar disorder continues with an unplanned pregnancy, the
newborn baby should have a full paediatric assessment, and social and
medical help should be provided for the mother and child
Pregnant women with acute mania or depression
Acute mania
If a pregnant women who is not taking medication develops acute mania, an
atypical or a typical antipsychotic should be considered. The dose should be
kept as low as possible and the woman monitored carefully.
If a pregnant woman develops acute mania while taking prophylactic
medication, prescribers should:
• check the dose of the prophylactic agent and adherence
• increase the dose if the woman is taking an antipsychotic, or consider
changing to an antipsychotic if she is not
• if there is no response to changes in dose or drug and the patient has
severe mania, consider the use of ECT, lithium and, rarely, valproate.
If there is no alternative to valproate the woman should be informed of the
increased risk to the fetus and the child's intellectual development. The lowest
possible effective dose should be used and augmenting it with additional
antimanic medication (but not carbamazepine) considered. The maximum
dosage should be 1 gram per day, in divided doses and in the slow-release
form, with 5 mg/day folic acid.
Depressive symptoms
For mild depressive symptoms in pregnant women with bipolar disorder the
following should be considered:
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• self-help approaches such as guided self-help and computerised CBT
• brief psychological interventions (including counselling, CBT and IPT)
For moderate to severe depressive symptoms in pregnant women with bipolar
disorder the following should be considered:
• psychological treatment (CBT) for moderate depression
• combined medication and structured psychological interventions for
severe depression.
For moderate to severe depressive symptoms in pregnant women with bipolar
disorder, quetiapine alone, or SSRIs (but not paroxetine) in combination with
prophylactic medication should be preferred because SSRIs are less likely to
be associated with switching than the tricyclic antidepressants. Monitor
closely for signs of switching and stop the SSRI if patients start to develop
manic or hypomanic symptoms.
Women who are prescribed an antidepressant during pregnancy should be
informed of the potential, but predominantly short-lived, adverse effects of
antidepressants on the neonate.
Care in the perinatal period
Women taking lithium should deliver in hospital, and be monitored during
labour by the obstetric medical team, in addition to usual midwife care.
Monitoring should include fluid balance, because of the risk of dehydration
and lithium toxicity.
After delivery, if a woman with bipolar disorder who is not on medication is at
high risk of developing an acute episode, prescribers should consider
establishing or reinstating medication as soon as the patient is medically
stable (once the fluid balance is established).
If a woman maintained on lithium is at high risk of a manic relapse in the
immediate postnatal period, augmenting treatment with an antipsychotic
should be considered.
If a woman with bipolar disorder develops severe manic or psychotic
symptoms and behavioural disturbance in the intrapartum period rapid
tranquillisation with an antipsychotic should be considered in preference to a
benzodiazepine because of the risk of floppy baby syndrome. Treatment
should be in collaboration with an anaesthetist.
Breastfeeding
Women with bipolar disorder who are taking psychotropic medication and
wish to breastfeed should:
• have advice on the risks and benefits of breastfeeding
• be advised not to breastfeed if taking lithium, benzodiazepines or
lamotrigine, and offered a prophylactic agent that can be used when
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breastfeeding – an antipsychotic should be the first choice (but not
clozapine)
• be offered a prophylactic agent that can be used when breastfeeding:
the first choice should be an antipsychotic
• be prescribed an SSRI if an antidepressant is used (but not fluoxetine or
citalopram)
Care of the infant
Symptoms including irritability, constant crying, shivering, tremor,
restlessness, increased tone, feeding and sleeping difficulties and rarely
seizures have been reported in neonates of mothers taking SSRIs. Many of
these symptoms are mild and self-limiting. In many cases these symptoms
appear causally related to antidepressant exposure although there is debate
about to what extent they represent serotonergic toxicity or a withdrawal
reaction.
Babies whose mothers took psychotropic drugs during pregnancy should be
monitored in the first few weeks for adverse drug effects, drug toxicity or
withdrawal (for example, floppy baby syndrome, irritability, constant crying,
shivering, tremor, restlessness, increased tone, feeding and sleeping
difficulties and rarely seizures). If the mother was prescribed antidepressants
in the last trimester, such symptoms may be a serotonergic toxicity syndrome
rather than withdrawal, and the neonate should be monitored carefully.
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Appendix One
NTIS guideline for the use of lithium in pregnancy (August
2007)44
PRIOR TO PREGNANCY:
• Women of childbearing age should be given lithium only for indications
where there is no alternative.
• There is a possibility that lithium therapy may lower fertility.
• Women should be informed of the possible teratogenic and fetotoxic
effects of such exposures.
• In women wishing to conceive - if possible, steadily decrease the dose
so that it is discontinued prior to pregnancy. Re-assess the need for
any concomitant medication and its potential fetal toxicity.
THE PREGNANT PATIENT:
• If the patient becomes pregnant whilst on lithium therapy; in some
women it is possible to decrease/discontinue lithium during the first
trimester. If lithium therapy needs to continue, serum levels should be
monitored so that the lowest possible effective dose is used.
• Monthly monitoring of serum levels may be required; weekly during the
last month of pregnancy and every 2 days perinatally.
NB Too low a concentration of lithium resulting in inadequate therapy
can be as harmful as too high a concentration.
• The maternal requirements for lithium change throughout pregnancy
and adjustment of the dose will be required for adequate control.
• The method of administration may need to be altered to avoid
fluctuations and pulses in maternal serum levels being transmitted to
the fetus - the total dose may need to be given in several equal doses
throughout the day.
• The maximum daily dose should be kept under 1g if possible.
Preferably no more than 300mg should be given as a single dose.
• Awareness of physiological disturbances which reduce lithium
clearance e.g.
(a) Sodium depleting diuretics should be avoided.
(b) Sodium-restricted diets should be used with caution.
(c) Gastrointestinal disturbances resulting in vomiting, diarrhoea,
dehydration and pyrexia may lead to sodium loss or impair renal lithium
clearance. If this occurs, serum lithium concentrations may need to be
adjusted.
• Maternal thyroid function should be monitored and where necessary
supplementation should be given.
• Antenatal fetal echocardiography performed at around 20 weeks
gestation may assist to quantify any risks of CVS defects.
DELIVERY- NEONATAL PERIOD:
• Lithium therapy should be withdrawn temporarily, if possible, around 710 days before delivery or just prior to labour to avoid excess levels in the
neonate.
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• As lithium is often used in combination with other drugs, the possible
adverse effects of these drugs either alone or in combination must be
considered.
• Neonatal toxicity may occur, e.g. hypotonia, cyanosis, 'floppiness', poor
thermoregulation and low APGAR scores. Appropriate neonatal support
should be readily available.
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