5.1 What is lithium?

Lithium is an element and in the same part of the periodic table as sodium and potassium. All of these elements are unstable and readily form salts. Lithium is found naturally in the form of lithium carbonate, which is dug out of the ground, mainly in Australia. There are good supplies throughout the world and provided that it is not all used up in a rush to make lithium-based batteries then there should not be a shortage in the foreseeable future.

5.2 How was lithium discovered?

John Cade, an Australian, is the doctor who is credited with introducing its modern use in psychiatry. In the 19th century, salts which included lithium were used for those suffering from mental illness, but this had not become accepted practice. Lithium had also been used as a diuretic and a salt substitute for those with cardiac failure earlier in the 20th century, but fell out of use because many patients ran into problems of toxicity. Cade was using lithium in an experiment on rats and thought that it had a calming effect on them and so a clinical trial in psychotic patients was undertaken. Lithium was found to be effective in the most active and agitated patients. Further studies in the 1960s and 1970s proved that it was an effective treatment for manic depression, though not without considerable initial scepticism.

5.3 How does lithium work?

We are not at all certain how lithium works. It is unlikely that it works directly on any neurotransmitter receptor in the brain, which is the putative mechanism of action of most psychotropic drugs (e.g. antipsychotics block dopamine receptors). Lithium tends to ‘look like’ calcium as a highly hydrated ion and may therefore affect the numerous actions of calcium on cells. The theory that is currently most popular is that lithium affects secondary messenger systems beyond the receptor including adenosine triphosphate (ATP) levels and G proteins.

5.4 How effective is lithium?

There are several ways to answer this question. Probably the simplest answer is that a third of patients who take lithium for manic depression have a very major, life changing benefit and their relapses are prevented, become much less frequent or much less severe. Another third will be likely to experience some benefit and notice a reduction in the severity or frequency of their illness, but still be experiencing significant symptoms. The other third really gain very little benefit from treatment with lithium and alternatives need to be considered (Prien et al 1973, Quitkin et al 1981).

The more statistical view of group effects is that lithium will reduce the rate of relapse by 20-30% (Fig. 5.1). The relapse rates in most trials are about 50% over a year on placebo and this is reduced to about 30% on lithium. However, it is difficult to translate this figure to individuals.

Fig. 5.1 Lithium reduces the relapse rate in manic depression; stopping lithium precipitates relapse, beyond natural history.

(Based on data from Schou 1993.)

5.5 What are the indications for lithium treatment?

The most common reason for prescribing lithium is as a prophylactic treatment in bipolar illness. Lithium is more usually used for the prevention of bipolar illness with mania rather than hypomania though it is effective in both disorders. It is also effective in the treatment of mania and bipolar depression. It can be used on its own for the treatment of bipolar depression but is more commonly prescribed in combination with an antidepressant.

Lithium is also useful in the acute treatment of unipolar depression in combination with an antidepressant. Lithium is usually prescribed for those patients who are suffering from depression but have had only a partial response to an antidepressant; lithium is added to augment this treatment. It is the only well-validated augmenting strategy for unipolar depression (Anderson et al 2000, Goodwin 2003). Lithium also has a place in the prevention of recurrent unipolar depression.

Lithium is occasionally prescribed for certain forms of headache (e.g. cluster headaches).

Lithium has also been tried in a number of other disorders but no method of treatment is proven–for example it has been tried as a way of reducing aggression in those with a learning disability or helping alcoholics to reduce their intake or prevent relapse.

5.6 Who should be taking long-term preventive treatment for bipolar disorder?

If someone has had even a single, severe, highly disruptive episode of mania or severe depression then it is tempting to suggest that they should take long-term treatment and indeed a few patients do this. However, after one episode it is very uncertain when the next episode will occur (though it almost certainly will occur at some time, see Q 2.18) and most people will not want to undertake a very long-term treatment at this stage.

For those who experience a recurrent bipolar illness the decision to take long-term treatment is based on the frequency of relapse, the severity and length of episodes and the impact of the illness on normal life.

One estimate is that if someone has just recovered from an episode of illness and had a previous one in the last 4 years, then that person should probably take a preventive treatment. This is based on the expectation that lithium will be likely to prevent at least one major relapse over the next 5 years.

5.7 What are the common side-effects of lithium treatment?

Most people taking lithium should expect to experience an increase in thirst and, accompanying this, an increase in frequency of urine. Often when patients initially start treatment they experience a diuresis.

The other common symptom is tremor which is an exaggeration of the normal essential tremor. It is very likely that patients will experience these two side-effects but usually at a mild level.

Another side-effect which is commonly reported is weight gain. It is difficult to know why patients gain weight. For some it is clearly related to them drinking a lot of sweet fluids which appear to slake the thirst better than water. In others the cause is rather obscure and they tend to gain weight even though they don’t feel that they are eating or drinking any more.

Many patients with manic depression, both when they are taking lithium and when they are not, complain of concentration and memory problems. It is not clear if lithium at therapeutic levels causes cognitive problems. Depression even at a low level can also affect cognition and disentangling these effects for individual patients is difficult.

5.8 Can lithium have long-term harmful effects?

The two major concerns about long-term lithium treatment are permanent effects on the thyroid and kidney. Hypothyroidism occurs in about 10% of those who take lithium and will usually persist even if the lithium is stopped.

Lithium can also affect the ability of the body to concentrate urine, which is the mechanism behind the excessive thirst and drinking that many patients experience. The biochemical explanation is that the kidney is not responsive to antidiuretic hormone (ADH). This effect usually reverses when lithium is stopped but can occasionally be persistent. There should be no permanent damage to the kidney if there are no episodes of lithium toxicity.

5.9 How dangerous is it?

Lithium poisoning through very high blood levels (3 mmol/l and higher) can cause permanent damage to the brain and kidneys and is potentially fatal. Damage to the brain often affects the cerebellum in particular and can leave patients permanently disabled. Likewise renal function can be permanently compromised by toxicity.

However, when the levels are kept below 1.2 mmol/l then lithium is very unlikely to cause long-term harmful effects on either the brain or the kidney. Usually those that suffer from toxicity do so because the levels have slowly gone up rather than in an acute overdose. Although lithium is obviously known to be dangerous at high levels it is surprising how rare overdoses of lithium seem to be, especially given that it is prescribed to a group that is exceptionally vulnerable to suicide (see Q 5.26). This may be because it is a very effective treatment and also that it may have a specific antisuicidal effect. However, the most serious adverse effects of lithium toxicity do seem to occur among those who deliberately take a large overdose of slow release tablets where the levels continue to rise long after ingestion even if they have vomitted.

5.10 What are the symptoms of lithium toxicity?

Levels can reach as high as 5.0 mmol/l and fatalities and permanent physical damage can be expected.

It is important that patients know the early symptoms of toxicity, particularly the gastrointestinal ones, so that if they do experience these symptoms they can take action early. Obviously a lot of people experience occasional diarrhoea and vomiting from food poisoning but consideration that this may be a symptom of lithium toxicity is important.

However, the levels can be quite confusing, as patients can still have prominent symptoms of toxicity even though the serum level is no longer high. This is because the lithium level in the tissues is still high.

5.11 What are the common reasons for patients becoming toxic?

5.12 What needs to be done prior to initiating lithium treatment?

The most important test is to ensure that renal function is normal. In physically healthy patients this can be done by checking their creatinine levels; in those whose renal function is impaired or likely to be impaired (e.g. the elderly) it is necessary to do a creatinine clearance test. Lithium can affect thyroid function (and abnormal thyroid function can also affect the course of bipolar illness) so checking thyroid function prior to initiation is also necessary.

Ensure that the patient has been given a leaflet outlining lithium treatment (see model in Appendix 3) as they will not remember enough from a conversation. Stress the symptoms of toxicity that need to be recognised, and also that careful use of lithium and good monitoring will prevent toxicity occurring. An example of specific instructions from the hospital about how to start treatment are shown in Figure 5.2.

Fig. 5.2 Example of a letter from a consultant to both GP and patient about starting lithium treatment.

The other important piece of information the patient should know is that this is a long-term treatment and sudden cessation of lithium can lead to rebound mania and so a worsening of the illness course (see Q 5.27). This means that the illness can be made worse by taking lithium intermittently than it would have been if the patient had never taken the treatment at all!

5.13 How is lithium treatment initiated?

Assuming that preliminary checks have been made (see Q 5.12) and renal function is normal, the usual routine for beginning lithium treatment would be to start at 400 mg at night and then check a blood lithium level at 5 days. It is likely that the initial target blood level will be 0.6 mmol/l and benefit will be judged at this level. If the blood level at 5 days comes back at less than 0.6 mmol/l the lithium dosage should be increased by 200 mg and checked again at 5 days. This process should be repeated until the desired level is reached. When a stable dose has been reached, continue to monitor every 2 weeks for 1 month, then monthly for a further 3 months and 3-monthly thereafter.

5.14 Why is lithium usually prescribed to be taken all at night?

There is no good therapeutic reason for taking lithium at night–it is no more effective then than if taken at any other time. However, side-effects are generally more prominent at higher blood levels which tend to be in the first few hours after taking the tablet (see Fig. 5.3), so it can be preferable for the patient to be asleep at this time. For compliance reasons taking tablets once a day is usually better (see Q 5.43).

Fig. 5.3 Daily variation in lithium level.

(Based on data from Bennie et al 1977.)

However, the main issue is arranging serum lithium estimations. These need to be taken 12 hours after the last dose so that if the lithium is taken in the evening it is relatively easy and convenient to do a blood test the following morning. The alternative of taking the tablets in the morning and doing blood tests in the evening causes not only logistic problems but also often results in samples being kept overnight which can affect other blood tests (e.g. potassium levels) that are done at the same time.

Some people find that splitting the doses of lithium between morning and evening is preferable, usually because this can reduce side-effects. This can make monitoring confusing if a blood test is taken only a couple of hours after the last dose which shows a high (peak) level. Patients should be asked to delay the morning dose until after the blood test, so that a trough level is measured.

5.15 What formulation of lithium should be prescribed?

Lithium is the same whatever formulation it comes in–tablets, slow release versions or liquid–carbonate or citrate. However, the dose is not interchangeable between different formulations and one cause of toxicity is a change of formulation. Different formulations have different bioavailabilities and if the formulation is changed then move to a lower dose and then monitor on a weekly basis until the levels are stable. The most common reason for doing this is changing to a liquid if the patient is not getting on well with tablets, as they are large tablets which can be difficult to swallow.

Currently in the UK lithium carbonate (Priadel) is the most commonly prescribed tablet. It is probably a good idea for all the patients in a practice to be taking the same formulation to reduce the possibility of prescribing errors.

5.16 What monitoring needs to take place while on lithium treatment?

When the patient is on a stable dose of lithium, checking lithium levels every 3 months is adequate; checking renal and thyroid function every year is also needed. Weight gain can be a problem with lithium and keeping an eye on this from the start rather than waiting until the patient has gained weight is worthwhile. There have been reports of hyperparathyroidism with lithium and some advocate checking calcium levels annually as well (Drug and Therapeutics Bulletin 1999).

5.17 Are lithium cards useful?

It is very helpful if patients keep a note of all their blood tests, so that whichever doctor they see there is a readily available record. This needs to include doses of drugs, dates of lithium levels, and also renal and thyroid function, thus allowing blood tests done either in the hospital or in general practice to be easily accessed.

Some pharmacies and clinics give out cards that are marked up to include spaces for the range of monitoring that is needed. Sometimes patients keep a notebook with various details about their treatment; no doubt some now use electronic means!

5.18 What blood levels should I be aiming for?

The therapeutic range that is routinely aimed for is 0.4-0.8 mmol/l in the serum at 12 hours after the last dose (Fig. 5.3). When lithium was first introduced into psychiatry, higher levels of up to 1.2 mmol/l were commonly used but over the years the level aimed for has tended to be lower. This is probably because doctors have become more concerned about toxicity, even though with care higher levels can be maintained safely.

Levels need to be at least 0.4 mmol/l in order for lithium to be an effective treatment, and no patient should be maintained below 0.4 mmol/l. Even levels of 0.4 mmol/l may not be enough and the usual practice would be to aim for a level of between 0.6 and 0.8 mmol/l. If this is not well tolerated a trial at lower levels down to 0.4 mmol/l is reasonable. If lithium is well tolerated at levels between 0.6 and 0.8 mmol/l but is only partially relieving or preventing symptoms, then higher levels up to 1.0 mmol/l (or even up to 1.2 mmol/l in acute treatment) may be needed and can be safely used with appropriate monitoring.