All You Need To Know About Lithium

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Lithium Pellets

Lithium Pellets

There are some suggestions from as early as the 2nd century AD that spring waters that were alkaline (which would be expected with a high concentration of lithium salts) were known to be of some use in the treatment of overactive states such as mania (1).

Lithium itself was isolated first by August Arfwedson in 1817. It was named lithium as it was found in stone – lithos being the Greek for stone. During the 1850s alkaline compounds, like lithium, were known to be of some use in preventing gout by interfering with the precipitation of uric acid in the blood and joints. At the time mania and melancholia were often seen as being part of the same family of diseases as gout and this led to the use of lithium for these conditions also. As early as 1880, the use of lithium in this manner led Carl Lange to suggest that it might have a role in preventing episodes of periodic depression.

Surprisingly, however, despite these discoveries and what would now appear to be correct hunches, lithium slipped out of use for mood disorders and had to be rediscovered in 1949. In part this was because of its side effects. In the middle of the 19th century, several investigators took lithium and noted that it caused increased urine flow, tremor of the hands and difficulties with memory or concentration, which led to wariness regarding its use. Later in the 1930s, it was used as part of a salt restriction diet in the United States and in many cases it caused such clear cut toxicity that its use was banned by the Foods and Drugs Administration (FDA).

In 1949, following observations that lithium had a tranquillising effect on laboratory animals, John Cade, in Australia, gave it to manic, depressive and schizophrenic patients. Je noted that it was particularly beneficial in mania. This led to its subsequent spread for use in the treatment of mania. In the early 1960s, the results of studies from Great Britain and Denmark appeared, which supported Lange’s 1880 hunch that lithium may be useful in the prevention of recurrent episodes of mania or depression.

The adoption of lithium by the psychiatric community has been a slow one. Several reason have been given for this. One is that the compound can have serious side effects. Regular blood lithium levels have to be taken in order to ensure that its side effects do not outweigh its benefits. A second reason put forward has been that lithium as an elemental compound is widely available and therefore no drug company stands to make much money out of it. It has certainly not been marketed as aggressively as other compounds. The third reason has been the general reluctance in the USA to prescribe lithium owing to its having been banned by the FDA in the past.

Table of Contents

What does lithium do?

Unfortunately we have no idea how lithium works. In this the position as regards the lithium is much the same for all antidepressants, including ECT. They all work, and indeed from perhaps the most specific set of treatments in psychiatry but there are at present no convincing theories about how they work. Lithium, in particular, affects a huge number of physiological processes throughout the body. The surprise, perhaps, is that it acts so widely throughout the body and yet is relatively specific in its therapeutic effects to one group of disorders.

Current uses for lithium

At present lithium is used regularly in the treatment of manic states. It is sometimes used to treat depression, often in conjunction with other antidepressants. It is perhaps most commonly used, however, to prevent recurrent episodes of mania or depression.

1) Mania

Lithium was first noted to be useful in states of mania. It appears to bring about a resolution of manic episodes in a way that is more specific than treatment with neuroleptic drugs (see The Management of Mania). But because treatment with lithium involves a physical screen of the patient beforehand, which takes some days, and because commitment to lithium afterwards would also involve ongoing blood tests and because the effects of lithium are somewhat slower in their onset than those of neuroleptics, the neuroleptics are typically used as a first line of treatment in mania.

It can be argued that the role of neuroleptics in mania, unlike that of lithium, is not specifically curative. Rather neuroleptics, particularly in the doses that are used in mania, provide a chemical strait-jacket (sometimes a necessary one) to curb behaviour, until such time as the disorder burns itself out naturally.

In contrast to the effects of neuroleptics in mania, there has always been a substantial body of opinion that has claimed lithium brings about a more specific response in mania. According to this view, patients will sometimes need to be controlled with neuroleptics for the first days in hospital but if they are prescribed lithium also, the mania will resolve much more specifically and cleanly than it would on neuroleptics alone – usually somewhere around day 10 after therapeutic blood levels have been reached (2,3).

2) Depression

Lithium also appears to have antidepressant properties. This is somewhat more controversial but, at present, a number of studies have shown that major depressive disorders respond to lithium, if treated with adequate doses. There have, however, been too few studies of this issue to adequately judge whether lithium is as effective as conventional antidepressants or whether it is effective for particular depressions.

Another line of evidence points towards an antidepressant effect of lithium. This is the recently introduced lithium augmentation treatment for refractory depressions. In cases of depression that prove resistant to conventional antidepressants, it is common practice now to add in lithium to the treatment the person is already on. It appears that in up to 50% of cases, the addition of lithium will bring about a response over the course of 2 or 3 weeks treatment (see All You Need To Know About Antidepressants).

3) Prophylaxis (prevention) of affective disorders

From the early 1960s, there has been a clear body of evidence pointing to a role for lithium in the prevention of episodes of mania and depression in bipolar affective disorders (that is affective disorders where subjects are liable to attacks of both mania and depression).

There is a considerable amount of evidence also indicating a role for lithium in recurrent depressions. The efficacy of lithium, however, seems to fall off once there are more than four episodes of depressive disorder a year.

The prevention of both episodes of mania and/or recurrent episodes of depression is, in practice, the principal indication for the use of lithium today. Many individuals who have been treated in hospital for mania are maintained on lithium for years or even decades afterwards in order to prevent recurrences in what is known to be a recurrent disorder.

At present there is great interest in the use of carbamazepine and sodium valproate for similar purposes – for the treatment of mania and depression and for the prophylaxis of recurrent affective disorders. There are some suggestions that subjects who prove unresponsive to lithium may be carbamazepine responsive (see The Management of Mania).

Dosage

Unlike most other drugs in use in psychiatry, there is a very clear window for lithium levels in the blood, below which level the drug appears not to work and above which the toxic effects outweigh the benefits.

It is generally held that in the acute treatment of mania or depression, a plasma level in the range of 0.9-1.4 mmol/l is needed. This may be achieved by taking a dose of lithium anywhere between 150 mg and 4.2 g per day. There is, therefore, a wide range in the amount of lithium that may be needed to produce therapeutic blood levels. Because of this, dosages are usually determined by screening blood levels.

For the prophylaxis (prevention) of affective episodes, the current wisdom is that blood levels between 0.4-0.8 mmol/l are adequate.

Because of the dynamics of lithium in blood, when determining blood levels it is usual to take a blood test 12 hours after the last dose of lithium taken. It is also necessary to wait 7 days after a change of dose to give plasma levels time to settle to a new steady state taking the next blood sample.

Because of its side effects, and in particular its effects on the kidney, there was until recently a tradition of giving lithium in divided doses during the day. Takers would be prescribed lithium tablets to take three or four times per day. Concern about kidney toxicity also led to the production of slow-release preparations of lithium. These are preparations where the capsule is taken but lithium is released steadily from it during the course of the day so that even more plasma levels are supposedly produced. It had become customary as well to give these slow-release preparations of lithium. These are preparations where the capsule is taken but lithium is released steadily from it during the course of the day so that more even plasma levels are supposedly produced. It had become customary as well to give these slow-release preparations in a divided dose – half in the morning and half in the evening.

However, there has recently been a change in the received wisdom. It now appears from animal studies that a single pulse of lithium, giving a high plasma level at one point in the day and falling off to a lower steady state level, is less toxic to the kidneys than having a relatively high level the whole time. The kidney appears to tolerate brief surges of lithium better than sustained moderate doses. The implication of this is that lithium perhaps should be given as a single dose at one point in the day and indeed that slow-release preparations. There has even been a suggestion that lithium could be given every 2 or 3 days than in a single dose every day (4).

Side Effects of Lithium

There is a considerable rate of non-compliance with lithium. The usual reasons given are that takers have intolerable side effects. The ones most commonly cited are weight gain, poor memory, tremor, thirst and tiredness. Other cited are that takers miss the highs that they normally get when not on lithium, or that they feel well and therefore see no need to continue with treatment while well. Or else people discontinue because they are bothered by the idea of drug treatment itself.

Tremor

Individuals taking lithium may develop a fine rapid tremor. This is, in itself, harmless although it may interfere with daily living by causing tea to spill from cups that are full, for example. It will usually clear up when the lithium is discontinued. It can be helped by the addition of a beta-blocker such as propranolol.

Thirst

Lithium causes people to feel thirsty and drink a lot. In actual fact what has been caused is an inability to concentrate urine which leads to the passing of greater volumes of urine than normal. It is this loss of water that subsequently leads to thirst. The reason for this is that lithium antagonises the action of a hormone called vasopressin, or antidiretic hormone (ADH), which acts on the kidney to promote the reabsorption of water from urine. Inhibiting ADH leads to an inability to concentrate urine, and a consequent loss of body water.

Urinary Frequency

This ADH antagonism leads to the passing of large volumes of urine and so a particularly troublesome complaint amongst lithium takers is that of having to get up during the night to micturate. Up to 50% of people who take lithium suffer this side effect. It is normally reversible once the lithium is stopped, but small proportion of patients may develop an incapacity to concentrate urine further when lithium is discontinued.

Dry Mouth

As lithium leads to fluid loss, one of the side effects is a dry mouth. Paradoxically, however, despite this fact, lithium leads to an increased production of saliva. It may also lead to an enlargement of the salivary glands.

Kidney Problems

Lithium, in a small proportion of people, can produce chronic kidney problems of a more serious kind. These are commoner in individuals who’ve been exposed to toxic doses of lithium at some point or other. At present the precise nature of the renal condition is uncertain, but it appears to involve the destruction of some kidney cells and a permanent impairment of the ability to concentrate urine.

Kidney function should therefore be tested before commencing on lithium and yearly thereafter. In particular, renal function should be tested in people who develop urinary frequency, especially frequency by night. In such objects the plasma level of lithium that should be aimed at is in the range of 0.4 – 0.6 mol/l.

Ordinarily, a simple blood test for urea and creatinine is an adequate screening procedure. In order to avoid kidney toxicity, it is important to attempt strenuously to avoid inadvertent overdosing.

Weight gain

Up to 50% of people who are put on lithium gain weight – around 10 kg, or more. The reasons for this weight gain are not entirely clear. It is likely that there are a number of factors.

One appears to be the thirst induced by lithium. Thirsty individuals, who drink anything other than just simple water, are likely to be consuming more calories than they would otherwise do. Current advice is that in cases of thirst, people taking lithium should stick to water only if possible.

It is also possible, however, that lithium increases appetite by reducing the effectiveness of insulin in the body. This could lead to low blood sugar levels, which stimulates appetite centres in the brain. This, however, is unclear. Another possibility, at present unproven, is that lithium may also lower basal metabolic rates which means that less food is burnt off as energy during the day.

Diarrhoea / constipation

Diarrhoea is commonly found in individuals on first taking lithium. Some people may continue to have somewhat looser stools than they would otherwise have, for as long as they remain on the drug. In the minority of individuals, however, there may be a constipation.

Diarrhoea is also a symptom of lithium toxicity. If an individual, who has not been suffering this side effect subsequently develops diarrhoea, lithium toxicity should be thought of. In the case of toxicity, the diarrhoea is likely to be accompanied by nausea, vomiting and a tremor.

Abdominal discomfort

Up to one-third of people taking lithium have a certain amount of abdominal discomfort for the first few weeks or few months of treatment. In a few cases this may be severe and will lead to the need to discontinue the drug. Also found is a sensation of bloating or painfulness in the lower abdominal area, one cause of which may be having a fuller than usual bladder owing to the effects of lithium on water concentration.

Loss of appetite / bad taste

Lithium in occasional cases may cause a loss of taste for food with a consequent loss of appetite.

Discoordination

A rarely mentioned but important side effect of lithium is that it may cause episodic discoordination or muscle weakness. Although rarely mentioned it seems that this side effect is not infrequent. As one individual writing on psychiatric drugs has put it, the first thing she knew about lithium discoordination was when she fell down the stairs (5). What appears to happen is that there’s a brief momentary loss of coordination and/or muscle strength. This leads to a feeling that a fall is imminent – a feeling that is often described as feeling dizzy or faint, but in actual fact it is neither dizziness nor faintness.

Skin and hair changes

Lithium may cause a variety of rashes, eruptions or irritations. The commonest problems are a simple skin rash, pustules or acne. Occasionally there are more exfoliative irritations that, in the extreme, may amount to a full blown psoriasis. These usually clear up once the drug is stopped, but recur if it is restarted. They appear to happen because of sensitivity to an accumulation of lithium in the skin.

In the normal course of events a tetracycline antibiotic would be given for an acne, but tetracyclines are contra-indicated with lithium because of potential kidney problems.

In about 5% of people there may be quite marked hair loss with lithium. This will usually clear up of its own accord even while staying on the lithium, but occasionally it will only clear up once a drug has been discontinued.

Quite rarely there are changes in the texture of the nails with pitting in the nails. This is a sign of a possible predisposition to psoriasis, and perhaps should lead to a discontinuation of treatment.

Heart

In general lithium has no adverse effects on the heart. In occasional cases where there is a pre-existing cardiac problem there may be some difficulties. Palpitations or shortness of breath, which develop while a person is taking lithium, should be investigated as to whether there may be some interaction with an undiagnosed cardiac condition.

White cells

Lithium in general leads to an increase in white cell numbers in the blood. This won’t be noticed by individuals taking lithium. It may sometimes be noticed by another doctor, leading them to wonder whether the person in question has an infection or not.

Hypothyroidism

Lithium can occasionally lead to hypothyroidism – underactivity of the thyroid gland. The signs of this are dry skin, dry hair, hoarseness, weight gain, hair loss, sluggishness, constipation and sensitivity to the cold. On blood tests, there are low thyroid hormone (T4 and T3) levels and increased TSH (thyroid stimulating hormone). The likelihood of either hypothyroidism or goitre is increased in women over the age of 45, and in all individuals who have thyroid antibodies (these are naturally present in up to 9% of the population). A goitre is an enlargement for a reduced output of thyroid hormone; it can lead to a normalisation of output, but indicates that the gland is struggling. A goitre may become obvious as a swelling at the base of the throat.

When screening for kidney functioning prior to commencing on lithium, it is routine practice also to monitor thyroid function. Both should be repeated anything from quarterly to yearly.

Hyperparathyroidism (overactivity of the parathyroid gland)

Generally speaking lithium leads to an increase in serum parathyroid hormone. This may in rare instances lead to excessive calcium levels of the blood, the symptoms of which are quite like the side effects of lithium itself – thirst, increased urine, loss of appetite and nausea.

Tiredness

A relatively common complaint on lithium is tiredness which, in some instances, may be quite marked. Tiredness can be difficult to assess as it’s possible that a recurrent depressive disorder may also give rise to these symptoms. Trying to tease apart what is caused by which can be rather difficult.

Tension / restlessness

In a small proportion of cases, lithium may give rise to tense, restless feelings. It may be difficult to decide whether lithium is causing the problem or not. One reason for this is that a taker of lithium may also be on antidepressants or neuroleptics, which can cause tension or restlessness (see Side Effects of Neuroleptics & Side Effects of Antidepressants).

Concentration / memory problems

There are a number of reports that lithium can interfere with memory and concentration. Again, this is difficult to judge as disturbances of memory and concentration occur in depression anyway. On the other hand, in volunteer subjects taking lithium, difficulties with memory and concentration have been reported to occur.

Confusion / distractibility

A prominent toxic effect of lithium is confusion and distractibility. Normally toxic effects occur when the lithium level goes over 1.5 mmol/l, but it is possible to have CNS toxicity in the presence of essentially normal plasma levels of lithium. In cases of toxicity, confusion and distractibility are likely to be accompanied by nausea and vomiting, as well as a variety of involuntary movements such as tremor, etc.

This toxicity is most likely to occur if the subject has recently been put on some other drugs, and in particular neuroleptics. It may also occur in the presence of an increased temperature of decreased fluid intake, because of an infection and dehydration. It can even happen if dehydration occurs because of an altered salt intake.

Lithium, however, may also cause confusion and distractibility as part of a dissociative reaction – see dissociative side effects of antidepressants.

Headache

Recurrent headaches are a rare side effects of lithium. If they occur they should be treated seriously. They may indicate raised intracranial pressure. This clears up once the lithium is discontinued, but must be detected as early as possible (see Side Effects of Antidepressants).

Sexual Function

Owing to a general difficulty in inquiring or volunteering information, little is known of the effects of lithium on sexual functioning. There is some suggestion that it may inhibit sexual interest and, in men, reduce the ability to maintain an erection or to achieve ejaculation. This, however, is uncertain and awaits further investigation.

Pregnancy

At present, the situation as regards lithium and toxicity to an unborn foetus is uncertain. Studies on animals and babies who have been delivered by mothers taking lithium, both at the time of conception and throughout gestation, suggest that there is a very small increased risk. The most likely side effect of taking lithium through pregnancy appears to be a slightly increased risk of heart defects in the child. At present, there is no reliable estimate of how likely this is. Accordingly the present position is that lithium, if indicated, can be continued at least during the early stages of pregnancy.

Later in the course of pregnancy, there are other arguments agains taking lithium. At this point, the risk to the foetus is minimal but it becomes difficult to determine exactly what plasma lithium levels mean, given that pregnancy brings about a large increase in body water. There is also an increased clearance of lithium through the kidneys.

There is furthermore a risk of causing lithium intoxication both to the mother and to the foetus, after delivery, as the extra body water shrinks rapidly on delivery and may cause, as a consequence, marked increases in plasma lithium levels. For these reasons, if possible, it may be prudent to discontinue lithium during pregnancy.

As regard breast feeding, lithium does get into breast milk. At present it seems that there is no risk to children reared on breast milk containing lithium. They seem to develop normally. If opting to breast feed while on lithium, it may make sense to take lithium once a day only and to ensure that feeds have taken place before the lithium dose, and that they do not take place during the 4-6 hours afterwards so as to ensure the lowest possible level in breast milk. Another possibility is to use a breast pump to collect milk at the safest times.

Contra-indications

Lithium is contra-indicated or should be taken with caution in:

  • Cardiac conditions, particularly where there is some abnormality to the cardiac rhythm or the conduction system of the heart.
  • Neurological disorders, such as Parkinson’s disease, Huntington’s chorea or any other organic neurological condition.
  • Kidney disease.
  • Thyroid disease.
  • Ulcerative colitis or irritable bowel syndrome.
  • Psoriasis, acne or hair loss.
  • Systemic lupus erythematosus.
  • Cataracts.

Interactions

1) Diuretics

There may be difficulties in combining diuretics and lithium. Diuretics lead to water loss, which may lead to an increase in lithium plasma levels. If it is necessary to use them, the lithium dose will often have to be reduced. The best diuretic to use with lithium is probably amiloride, as it appears to be the least likely to lead to any inadvertent lithium toxicity.

2) Painkillers

Lithium should also be combined cautiously with most common painkillers, including aspirin, diclofenac, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, mefenamic acid, naproxen, phenylbutazone, piroxicam, and tiaprofenic acid. These are all widely available over the counter for headaches, cold and flu. They are also commonly used in the treatment of arthritic conditions. Most of them lead to increased lithium levels and, therefore, the possibility of lithium toxicity.

For mild and occasional aches, pains and fever the best painkilling agent to use is probably paracetamol. For more severe painful or rheumatoid conditions it appears that the best non-steroidal treatment is sulindac, which appears to lower lithium levels, if anything. All of the others are usable, but their use would require extra monitoring of plasma lithium levels to ensure that toxicity is not inadvertently induced.

3) Others

In general, lithium antagonises the effects of most social drugs. Both the effects of amphetamines, cocaine and other stimulants are reduce. It also antagonises the effects of alcohol.

Tea and coffee, however, and related drugs such as theophylline, which are used for asthma, may lead to a lowering of lithium levels.

Lithium may also interact with calcium channel blockers, used to treat angina, hypertension or cardiac arrhythmias, and with angiotensin converting enzyme (ACE) inhibitors, used in the treatment of hypertension.

References

  1. Johnson FN: Depression and mania: modern lithium treatment. Oxford: IRL Press; 1987.
  2. Schou M: Phases in the development of lithium treatment in psychiatry. In The neurosciences: paths of discovery, vol 2. Edited by Samson F, Adelman G. Boston: Birkhauser; 1992: 149-166.
  3. Healy D, Williams JMG: Moods, misattributions and mania. Psychiatr Dev 1989, 7:49-70.
  4. Abou-Saleh MT: The dosage regimen. In Depression and mania: modern lithium treatment. Edited by Johnson FN. Oxford: IRL Press; 1987:99-104.
  5. Blaska B: The myriad medication mistakes in psychiatry: a consumer’s view. Hosp Community Psychiatry 1990, 41:993-998.

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