Alternative drugs to lithium

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Anticonvulsant drugs, which were originally developed for the treatment of epilepsy, are often used as mood stabilisers, to treat bipolar disorder (manic depression). Two of these drugs, carbamazepine and valproate, are well established as alternatives to lithium and are licensed for this use. They are particularly effective in people with rapid cycling bipolar disorder (four or more episodes per year).

In addition, another anticonvulsant, lamotrigine, is also increasingly being used in the same way, although it is not currently licensed for bipolar disorder in the UK.

Other drugs licensed to treat mania are the antipsychotics olanzapine (Zyprexa) and risperidone (Risperdal) which may be combined with lithium or valproic acid. Older antipsychotics are also used, but high doses of haloperidol, fluphenazine or flupentixol may be hazardous when used with lithium. For more information about antipsychotic drugs, see Mind’s booklet Making sense of antipsychotics (major tranquillisers).

Carbamazepine (Carbagen SR, Tegretol, Tegretol Retard and Teril Retard)

When not to take carbamazepine
Carbamazepine should not be taken by people with certain heart conditions; a history of bone marrow disease; or prophyria (an inherited condition). It should be avoided in pregnancy as it may cause defects in the foetus, including spinal defects. It should also be avoided while breast-feeding.

Cautions
Carbamazepine should be used with caution in people with kidney or liver problems, heart disease, blood disorders, glaucoma, and those who abuse alcohol. In diabetics it may increase the amount of sugar in the urine.

Side effects of carbamazepine
(Commonest first) nausea and vomiting, dizziness, drowsiness, headache, unsteadiness, confusion and agitation (older people), visual disturbances such as double vision; constipation or diarrhoea, loss of appetite, skin rash, blood disorders; rarely jaundice, hepatitis, and kidney failure; a severe reaction with ulceration and fever; hair loss; blood clots; joint pain; fever; swollen glands; heart problems; movement disorders; pins and needles; depression; impotence; breast growth; lactation; aggression; psychosis; sensitivity to sunlight; breathing or lung problems; low blood sodium; fluid retention; disturbances of bone metabolism.

Is it safe to take carbamazepine with other medicines?
Carbamazepine affects the metabolism of many other drugs. If you are taking any other medication at the time when carbamazepine is prescribed, including over-the-counter and herbal medicines, it is very important that you discuss this with your doctor.

Carbamazepine can make oral contraceptives less effective, so your doctor may suggest you change to a different type of pill, or you may want to consider alternative methods of contraception.

If carbamazepine is taken with antipsychotics or lithium it may increase the side effects.

It should not be used with MAOI (monoamine oxidase inhibitor) antidepressants or within two weeks of taking them. It may reduce the effectiveness of tricyclic antidepressants and some antipsychotics, such as haloperidol. Blood levels of carbamazepine are increased by fluoxetine (Prozac) and fluvoxamine (Faverin).

Dose
The usual starting dose for manic depressive illness is 200mg twice a day, increasing to 600-1,000mg/day, to give a blood level of 8-12mg/l. Modified release tablets (Carbagen SR, Tegretol Retard or Teril Retard) are normally prescribed, and doses increased slowly. Once the dose is established, blood levels should be checked every three to six months. The maximum dose is 1.6 g (1,600mg) daily.

Carbamazepine comes as tablets, chewtabs, liquid, and suppositories. The modified release forms are all tablets.
 
Semisodium valproate (Depakote)

Valproate is licensed for the treatment of manic episodes in bipolar disorder. It is increasingly being used in preference to lithium as a first-line treatment for bipolar disorder.

When not to take valproate
Valproate should not be given to people who either have liver disease, or have a family history of liver disease. (Liver function should be monitored before starting treatment, and liver and kidney function and blood should be checked regularly.) It should be avoided in pregnancy as it may cause defects in the foetus, including heart defects, spinal defects, hare lip and cleft palate, and liver problems. It should also be avoided while breast-feeding.

Cautions
Valproate should be used with caution in people with kidney problems.

Side effects of valproate
The most common side effects of valproate are stomach irritation, feeling sick, unsteadiness, shaking, increased appetite and weight gain. Less common effects are hair loss, fluid retention (puffy hands and feet), blood disorders, liver problems (fatal liver failure has occurred). Rarer side effects are rashes, sedation, aggression and hyperactivity, pancreatitis, dementia, irregular or loss of periods, breast growth, hearing loss, abnormal kidney function (resulting in the loss of essential minerals), skin ulceration, hairiness, acne.
 
Is it safe to take valproate with other medicines?
Valproate may increase blood levels of MAOI (monoamine oxidase inhibitor) and tricyclic antidepressants, and may also increase the activity of aspirin. They are not thought to affect the contraceptive pill. You should make sure your doctor knows all the other medicines you are taking, including over-the-counter and herbal medicines, at the time when these drugs are prescribed.

Dose
Initially 750mg/day in two to three divided doses (ie 250mg three times/day), increased according to response. Usual dose 1-2g/day; however, the datasheet suggests that daily dosage should be established according to age and body weight. Individual sensitivity to this drug may be very variable. It is not recommended for children under 18.

Valproate comes as tablets.

Lamotrigine (Lamictal)

Lamotrigine is not licensed in the UK for treating bipolar disorder, so the information provided by the drug company relates only to its use in epilepsy. It is approved for use in bipolar disorder in the USA. Several different research studies have shown that in addition to mood stabilising effects, lamotrigine has antidepressant effects as well.

Cautions and side effects
This drug should be used with caution in people with liver or kidney problems, and during pregnancy and breastfeeding.

As its main side effect is rashes, which affect 1 in 10 people, it is usually started cautiously, with a gradual increase in dose; this decreases the likelihood of the rash. While most rashes are mild, a rash may occur as part of a hypersensitivity syndrome associated with various symptoms including fever, facial oedema (puffiness) and abnormalities of the blood and liver. The syndrome is potentially life-threatening. You should go to a doctor immediately if you develop a rash or fever while taking this drug and stop taking it if no other explanation for your symptoms can be found. Many people with a mild rash can continue to take lamotrigine, sometimes together with an antihistamine.

A rash is more likely to develop when the initial doses of lamotrigine are high or when lamotrigine is too rapidly started when someone is already taking valproate.

Other side effects: fever, feeling unwell, flu-like symptoms, sleepiness, lymph node problems, blood disorders, blistering of skin, sensitivity to sunlight; double vision, blurred vision, conjunctivitis, dizziness, drowsiness, difficulty sleeping, headache, unsteadiness, tiredness, gastrointestinal disturbance (including vomiting and diarrhoea), irritability and aggression, shaking, agitation, confusion; headache, feeling sick.

Is it safe to take this drug with other medicines?
Lamotrigine interacts with carbamazepine so that blood levels of lamotrigine are somewhat lower in people taking carbamazepine than in those not taking carbamazepine.

Valproate may double blood levels of lamotrigine, therefore if the two drugs are taken together, the initial dose of lamotrigine should be halved.

Its effect may be reduced by antidepressants.

The drug has an important interaction with oral contraceptives so that the dosage of both drugs needs to be carefully adjusted. Women are advised to use alternative methods of contraception if possible.

Dose
The dosage recommendations relate primarily to its use for epilepsy. The starting dose is 25mg/ day for 14 days, increased to 50mg/day for a further 14 days, then increased by a maximum of 50-100mg every 7-14 days. The usual maintenance dose (for epilepsy) is 100-200mg per day as one or two doses.

Lamotrigine comes as standard tablets and dispersible tablets.

References

British National Formulary 51, March 2006.
The Bethlem and Maudsley NHS Trust Prescribing Guidelines, 1999.
Fundamentals of Clinical Psychopharmacology, ed. Ian M Anderson and Ian C Reid, Taylor and Francis, 2004.
Summaries of product characteristics on http://emc.medicines.org.uk/
www.psycheducation.org/depression/meds/lamotrigine.htm
www.psycom.net/depression.central.lamotrigine.html

Useful organisations

Psychiatric drugs helpline
tel: 020 7919 2999 (Mon to Fri 11am to 5pm)

MDF The Bipolar Organisation
Castle Works, 21 St. George's Road, London, SE1 6ES
tel: 08456 340 540; fax: 020 7793 2639
email: mdf@mdf.org.uk
web: www.mdf.org.uk

Further reading

Mind factsheets
Lithium during pregnancy, childbirth and afterwards

Mind booklets
Making sense of antipsychotics (major tranquillisers) (Mind 2004)
Making sense of lithium (Mind 2004)
Understanding manic depression (Mind 2003)

This factsheet was written and updated by Katherine Darton, Mind Information Unit, April 2006.