Lithium

15/10/2010Recent newsNo Comments

Why is lithium treatment difficult?
Lithium has a narrow therapeutic range. Its target levels are 0.4-1.0mmol/l, with the lower end required in older patients and for maintenance therapy. Toxicity is seen above 1.5mmol/l, and plasma levels over 2.0mmol/l can be fatal. Medicines adherence is low, and the drug can take a year to have a prophylactic effect.

What are the side effects?
Common effects experienced when the drug is used within its therapeutic range include thirst, increased urination and weight gain.

Less common side effects include: blurred vision, slight muscle weakness, occasional diarrhoea, fine hand tremor, feeling ‘a bit ill’. These side effects can indicate that the dose is too high.

Missed doses
If a dose is missed by less than three hours, it should be taken as normal. If missed by more than three hours, the dose should be omitted.

Lithium is most commonly used in bipolar disorder, but also in depression, premenstrual tension and unlicensed in cluster headache prophylaxis.1 It was the first effective mood stabiliser, with its antimanic properties first discovered in 1949.2 Despite over 50 years of use, the mechanism of action is still not fully understood.3

As lithium resembles sodium in excitable tissues, it penetrates them via fast voltage-sensitive channels responsible for action potential generation. It is not pumped out to the same degree as sodium and therefore accumulates inside these cells to a greater extent, resulting in partial intracellular potassium loss and partial cell depolarisation.4

Lithium acts selectively in the brain and kidney.4 Acutely, lithium appears to increase brain noradrenaline and serotonin turnover, but inhibit its release on cell depolarisation by noradrenaline-sensitive adenylyl cyclase inhibition, which may produce its antidepressant and antimanic effects.5 It also affects various second-messenger system enzymes, the most well-documented being inositol phosphates.

Its long-term mechanism of action may be due to its alteration of protein kinase C-mediated signalling, changing gene expression and protein production implicated in long-term neuroplastic events.5

Treatment
Lithium is used for the acute and prophylactic treatment of bipolar disorder. It is also used to augment unipolar depression treatment after failed antidepressant therapy, or for prophylaxis of unipolar depression. Lithium has slower onset of action than valproate or other antipsychotics7 and can take six to 12 months for a full prophylactic effect to occur. Acutely ill patients, however, usually respond within three to seven days.

Long-term pharmacological treatment usually lasts for at least two years after an episode of bipolar disorder, or up to five years if there are risk factors for relapse.10 There is a high rate of non-compliance (18-53 per cent) with reasons including side effects, dislike of taking mood-controlling medication and being identified as having a chronic illness.6 However, it has been shown that lithium therapy reduces overall relapse risk by 30-40 per cent,3 so it is important that patients continue treatment.

Lithium has a narrow therapeutic range. Its target levels are 0.4-1.0mmol/l, with the lower end required in older patients and for maintenance therapy. Toxicity is seen above 1.5mmol/l, and plasma levels over 2.0mmol/l can be fatal and require urgent treatment.

Nice states a target of 0.6-0.8mmol/l should be aimed for in long-term treatment, although a range of 0.8-1.0mmol/l may be of benefit in patients with predominiantly manic symptoms, and those who have previously relapsed while on lithium.10

Patients are usually started on a dose of 750-1,000mg daily in divided doses, which is then titrated to the appropriate concentration.6 The maintenance dose is usually 200-400mg (carbonate salt), which is taken at night.9 Brands are not bioequivalent (see table 2), so must be brand prescribed.

Lithium should usually be reduced over at least four weeks10 as studies have shown 50 per cent of patients relapse, mostly into mania rather than depression, within five months of rapid discontinuation.6 There does not appear to be evidence of rebound psychosis or withdrawal syndrome. If a dose is missed by less than three hours, it should be taken as normal. If missed by more than three hours, the dose should be omitted and the next taken as normal.11

Side effects
Side effects can start in the first few weeks of treatment, but often reduce with time. Common effects experienced when the drug is used within its therapeutic range include thirst, increased urination and weight gain.

Less common side effects include blurred vision, slight muscle weakness, occasional diarrhoea, fine hand tremor and feeling ‘a bit ill’.

These side effects can indicate that the dose is too high and should be reduced.
Patients should seek urgent medical attention if any side effect becomes more pronounced, or if the patient becomes muddled or confused, as this indicates plasma levels are too high.7

Lithium inhibits T3 and T4 secretion, and can result in hyper- and hypothyroidism. Other side effects include ECG changes; a diabetes insipidus-like syndrome; reduction in bone calcium;8 skin rashes; a metallic taste. Mild cognitive and memory impairment can also occur.

Lithium increases foetal malformation risk, with the risk greatest in the first trimester, but it has been deemed safe after 26 weeks and is safer than other mood stabilisers.3 It is contraindicated in breastfeeding. See table 1 for a list of possible drug interactions.

Pharmacokinetic profile

* Has a plasma halflife of eight to 55 hours6 (which is increased in older patients and patients with reduced renal function). The halflife is around 24 hours for most patients.
* Takes five to seven days to reach steady state.
* Is readily absorbed from the gastrointestinal tract and distributed through the body over several hours.
* Is almost exclusively excreted by the kidneys, but also in sweat and saliva.
¥ Is not plasma protein bound.
* Crosses the placenta.
* Is excreted in breast milk.

Monitoring
Plasma levels should be measured one week after initiation and one week after every dose change until levels are stable, then every three months,10 with blood taken 12 hours after the last dose.

Patients must also undergo general and specific monitoring to ensure safe treatment (see table 3) and because bipolar patients have a higher morbidity rate than the general population.

Early features of overdose are non-specific, such as apathy and restlessness, and can be confused with mental health changes due to depression. Tremor, twitching, vomiting, weakness and ataxia can follow. Severe poisoning is associated with electrolyte changes, dehydration, convulsions, coma and renal failure.

Concentrations over 2.0mmol/l are associated with serious toxicity, requiring haemodialysis if renal failure or neurological symptoms are present.

Overdose
Deliberate acute overdose may not manifest until more than 12 hours after the medicine has been taken due to slow entry of lithium into the tissues, or staggered absorption with modified release preparations.1 An overdose can result in higher concentrations without toxicity features. Increasing urine output by increasing fluid intake should resolve the overdose;1 diuretics should never be used. Gastric lavage can be considered if the patient presents within one hour of acute ingestion.

Supportive treatment, with special attention to electrolyte balance, renal function and controlling convulsions, is required in patients who have taken an overdose. Serum lithium should be monitored for at least seven days as a rebound rise is possible due to delayed tissue release.12

The National Patient Safety Agency released an alert ‘Safer lithium therapy’ in December 2009, detailing the steps required by all involved in lithium treatment to help ensure patient safety. The report’s recommendations must be implemented by December 2010.

The main points for action are:

* monitoring should be according to Nice Guidance 38
* systems must be in place to ensure blood test results are communicated between laboratories and prescribers
* patients must receive verbal and written information throughout treatment
* patients must receive a record book to record lithium levels and other clinical test results
* prescribers and pharmacists must check that bloods tests have been carried out and it is safe to issue/dispense medications
* systems must be in place to deal with medication interactions.

Pharmacists should ask patients about their last lithium blood test and results. If unavailable, medication should not be withheld (unless clinically necessary), but the prescriber should be informed the medication was supplied without blood test data being available.9

Lifestyle advice
* Drink plenty of water or other unsweetened drinks, increasing in hot weather or when active.
* Maintain a stable intake of caffeinated drinks (increasing such drinks results in increased urination and reduced lithium blood levels).3
* Eat a balanced diet.
* Do not abruptly change the amount of salt in the diet – a low salt diet will increase lithium levels.
* Eat regularly.
* Drink alcohol as per national guidelines.
* Exercise as per current guidelines.
* Learn to recognise signs of mood changes and have plans in place to avoid full-scale change.
* Avoid stressful situations that can trigger manic or depressive episodes, or at least learn how to deal with them to help prevent this occurring.
* Try to have someone to confide in and maybe give a list of signs/symptoms to alert others to impending mood changes.
* Make time to relax.
* Keep occupied – activity planning can help.

Rosemary Blackie MRPharmS is a community pharmacist in Sheffield.

Reflect
What are the most common side effects of lithium? Which drugs can increase lithium levels? Why is it important for those taking lithium to maintain a stable intake of caffeinated drinks?

Plan
This article discusses the drug lithium and includes information about its action, side effects and the monitoring of patients who are taking it. It also describes interactions with other drugs, overdose, the NPSA safer lithium therapy alert and lifestyle advice for patients.

Act

• Find out more about lithium from the Clinical Knowledge Summaries website at http://tinyurl.com/lithium01.
• Update your knowledge of bipolar disorder from the Royal College of Psychiatrists website at http://tinyurl.com/lithium02.
• Read more about lithium overdose on the MHRA website at http://tinyurl.com/lithium03.
• Revise your knowledge of the NPSA safer lithium therapy alert by reading the information on the NPSA website and the standard operating procedure for supplying lithium at http://tinyurl.com/lithium04.

Evaluate
Are you now confident in you knowledge of lithium and its side effects and interactions? Are you familiar with the safer lithium therapy guide? Could you advise patients about lithium therapy?

References

1. British National Formulary Number 58 September 2009
2. Lithium Patient UK www.tinyurls.co.uk/W7778
3. Bipolar Disorder (manic depression) The Royal College of Psychiatrists www.tinyurls.co.uk/P7779 accessed July 2010
4. Pharmacology Chapter 29 Dugs used in affective disorders Rang, Dale and Ritter Third Edition
5. Basic and Clinical Pharmacology 11th Edition (2009) Chapter 29 Antipsychotic Agents and Lithium Herbert Meltzer www.tinyurls.co.uk/L7780 accessed via the RPSGB online full text books
6. Therapeutic drug monitoring of psychotropic medications British Journal of Clinical Pharmacology,49, 303-312
7. Understanding Bipolar Disorder Pharmaceutical Journal April 2010 www.tinyurls.co.uk/H7781
8. Lithium GP Notebook www.tinyurls.co.uk/U7782
9. Patient Safety Alert NPSA 2009/PSA005 Safer Lithium Therapy Supporting Information NPSA December 2009
10. Bipolar Disorder Nice Guideline 38 Quick reference guide July 2006
11. Making Sense of Lithium and Other Mood Stabilisers MIND www.tinyurls.co.uk/V7783 12. Camcolit SPC
13. Priadel SPC
14. Li-Liquid SPC
15. Liskonium SPC