Lithium Prescribing and Monitoring in Clinical Practice – A Practical Guide

CLINICAL PROFILE OF LITHIUM

Acute mania:

Several clinical trials have shown lithium monotherapy is significantly better than valproate, olanzapine, or risperidone. [2]

However, a response to lithium monotherapy is longer than most atypical antipsychotics (6-10 days), and therefore lithium is often administered in combination with an antipsychotic for faster symptom relief. [2]

Acute bipolar depression:

Lithium is evidence-based in the management of acute bipolar depression, however, the evidence base is less impressive than that for Mania.

Nonetheless, it is included as an option in the recent RANZCP guidelines for the treatment of acute bipolar depression. [3]

The paucity of a strong evidence base may be because lithium’s antidepressant effect can take 6-8 weeks, which may be perceived by patients as lacking efficacy resulting in high drop-out rates which can skew trial results.

Prophylaxis and Maintenance:

Lithium monotherapy is effective against manic, depressive, mixed relapse and suicidal behaviours. It also has better evidence for the prevention of new episodes than other agents and has more substantial evidence base documenting the risks of prolonged exposure. [4]

The real world effectiveness of Lithium was demonstrated in the BALANCE study (Bipolar Affective Disorder: Lithium/Anticonvulsant Evaluation). [5]

More recently, the real-world effectiveness study in a Finnish cohort of 18018 patients found that lithium use was associated with the lowest risk of rehospitalisation because of mental or physical illness compared to antipsychotics or other mood stabilisers. [6]

Rapid cycling and mixed states

Lithium is less effective in rapid cycling and mixed states although it decreases symptom severity and reduces morbidity.

Lithium therapy, therefore, is advocated in rapid cycling as combination therapy with other psychotropics.

Anti suicidal properties:

Patients who are compliant with lithium show a reduction in suicidal behaviour even in the absence of mood stabilisation likely through the reduction of aggression and impulsivity.

The two reviews by Cipriani et al., overwhelmingly highlight lithium’s anti-suicidal effect which showed a risk reduction of 60% for suicide and 70% for self-harm. [7]

A recent systematic review specifically examining interventions in Bipolar disorder in the early phases of treatment concluded that lithium treatment may be associated with a lower risk of recurrence of mood episodes compared with several other agents among those in the early course of illness. [Ratheesh et al, 2023]

Compared to antipsychotics which have a role in acute treatment, lithium may have value in maintenance treatment in early illness course over antipsychotic medications.

LITHIUM ABSORPTION AND BIOAVAILABILITY

After a single dose, the body distributes lithium throughout most of the tissues and fluids of the body.

Besides the serum and the brain, lithium is found in the bone, thyroid, and red blood cells.

Moreover, magnetic resonance spectroscopy shows that brain concentrations of lithium are about half those found in the serum (0.5:1 ratio of Brain : Serum lithium concentrations). Lithium peaks in the brain approx 24 hours after ingestion. [8]

Lithium is exclusively excreted through the kidneys without undergoing any known in vivo metabolic transformations. Approximately, 80% of administered lithium is re-absorbed by passive diffusion in the proximal tubes, although there is high inter-individual variability.

The half-life of lithium is between 18-36 hours.

The absorption and bioavailability of lithium differs based on the various formulations available.

Lithium is administered as a salt in the form of lithium carbonate, lithium citrate, lithium chloride or lithium sulfate. 

Lithium is available in Australia as:

• Immediate-release lithium carbonate capsules – 250 mg tablets. Peak concentration is reached 1 to 3 hours with a bioavailability of 95% to 100%
• Extended-release lithium carbonate – 450 mg tablets. Peak concentration is reached in 3 to 6 hours with a bioavailability of 60% to 90%

Lithium citrate oral solution is also available in other countries.

LITHIUM DOSING

Due to the delay (7-10 days) in the anti-manic effect of lithium, it is usually combined with an antipsychotic in the treatment of mania which provides more acute symptom relief.

Lithium can be prescribed as a single dose or multiple dose schedule. A single dose regime can be associated with higher peaks in plasma lithium levels (associated with side effects) and deeper troughs (higher likelihood of breakthrough symptoms).

After initiation, lithium levels should be checked after 7 days, then 7 days after every dose change until the desired level is reached. [The Maudsley Prescribing Guidelines in Psychiatry, 12th edition] (See levels below)

In the elderly or in patients with impaired renal function, the time to steady-state increases, implying that the lithium level should also be measured after 10‐12 days.

Advantages of single dosing schedule:

• Since lithium has a longer half-life in neural tissues, once-daily dosing may be sufficient to maintain an effective brain lithium concentration for prophylaxis.
• A single dosing schedule causes less polyuria and decreases the chances of permanent renal damage.
• Since lithium clearance is lower overnight, a single daily dose can be reduced by 25% which reduces the likelihood of side effects which in turn can enhance compliance.

LITHIUM LEVELS - SAMPLE COLLECTION

The efficacy of lithium correlates with serum lithium levels (trough levels). (See later).

Trough levels are best measured when tested just before the next dose.

The consensus from the International Society of bipolar disorder (ISBD) and International Study Group on Lithium (IGSLI): [Nolen W et al., 2019]

Twice daily dosing:

• Sampling should be in the morning 12 ± 1 hrs after intake of the (last) evening dose and before the morning dose.

Once-daily dosing in the evening:

• Sampling should be in the morning, 12 + 1 hours after intake of the evening dose.

A cross-sectional study, however, suggested that in patients with once-daily dosing, a 24-hour post-dose may offer a more accurate trough level and may prevent underdosing. [Reddy S & Reddy S, 2014]

The study showed that measuring serum lithium levels at 12 hrs in case of OD dosing gave a value 1.3 times higher than the actual trough value.

Thus in a patient taking a once-daily evening dose, to avoid the inconvenience of an evening blood test, a 12 hr sample can be obtained and then adjusted by 1.3 to calculate an actual trough level at 24 hours.

SPECIAL DOSING REQUIREMENTS

The dosing properties of lithium can vary in special situations due to its potential for toxicity:

Pregnancy:

Lithium in pregnancy should be used only after a careful risk-benefit analysis.

Lithium can cross the placenta and can increase the risk of Ebstein’s anomaly with exposure in the first trimester (4-12% risk).

Key points about Lithium in Pregnancy: [Fornaro M et al., 2019]

• Lithium prescribed during pregnancy was associated with higher odds of any congenital anomaly (NNH -33; Odds ratio 1.810).
• Odds of a cardiac anomaly (NNH -71; Odds ratio – 1.86).
• Lithium exposure during the first trimester was associated with higher odds of spontaneous abortion (NNH -15; Odds ratio 3.77).

Comparing lithium-exposed with unexposed pregnancies, significance remained for any malformation (exposure during any pregnancy period or the first trimester) and cardiac malformations (exposure during the first trimester), but not for spontaneous abortion (exposure during the first trimester) and cardiac malformations (exposure during any pregnancy period). [Fornaro M et al., 2019]

• Lithium was more effective than no lithium in preventing postpartum relapse (NNT -3; Odds ratio – 0.16 ).
• The qualitative synthesis showed that mothers with serum lithium levels <0.64 mEq/L and dosages <600 mg/day had more reactive newborns without an increased risk of cardiac malformations.

The risk associated with lithium exposure at any time during pregnancy is low, and the risk is higher for first-trimester or higher-dosage exposure. Ideally, pregnancy should be planned during remission from bipolar disorder and lithium prescribed within the lowest therapeutic range throughout pregnancy, particularly during the first trimester and the days immediately preceding delivery, balancing the safety and efficacy profile for the individual patient. [Fornaro M et al., 2019]

During the third trimester, lithium clearance increases by up to 50% due to increases in glomerular filtration rate, which can result in recurrence of manic symptoms.

Pregnant women need to reduce the dose of lithium 1-2 days before delivery to avoid lithium toxicity post delivery as the maternal blood volume, and renal filtration rate rapidly returns to normal. [8]

Post delivery, mothers should reinstitute treatment immediately as the risk of relapse is high. (80% risk of relapse)

Lithium is excreted in breast milk, and infant levels may be 30-50% that of the mother. Thus the infant should be monitored for signs of toxicity should the mother continue to breastfeed.

Advanced age:

The co-morbid physical and psychiatric changes in the elderly can increase the risk of adverse events.

It is recommended that a lower starting dose (reduction of 25-35% in dosages) and slower dose titration be used.

This is primarily due to reduced renal function in conjunction with poor water retention resulting in less lithium excreted and poorer distribution of lithium through the body. [9]

Renal disease:

Renal insufficiency and nephritic syndrome are a relative  contraindication, and the elimination half-life reported in patients with renal disease is increased from 24 hours up to 40-50 hours.[8]

It is recommended that patients’ renal function be closely monitored during lithium therapy.

Obesity:

Lithium clearance is significantly greater for obese patients than for non-obese. This was shown to correlate well with the level of fat-free mass rather than total bodyweight.

Therefore, it is recommended that treatment starts with smaller initial doses of lithium, which are closely related to the patient’s ideal bodyweight, and then to administer larger doses based on a patients’ actual bodyweight. [10]

LITHIUM SIDE EFFECTS

When evaluating adverse reactions to lithium, the following three factors should always be considered:

1. Misattribution of psychiatric symptoms for drug-related side effects
2. Effect of the depressed mood state increasing subjective analysis of side effects
3. The additive effect of multiple pharmacotherapies on side effect rates

Common side-effects of lithium toxicity include:

Gastrointestinal side-effects :

Typically nausea, vomiting, indigestion, diarrhoea, and abdominal cramping are relatively common particularly in the initial stages of therapy.

Administration of lithium after meals, using a multiple daily dose regimen, or using sustained-release formulations can reduce nausea.

Neurological side-effects:

Fine tremors (that are distinct from PD-related tremors) and impaired movement, is often induced by lithium therapy.

Extended-release formulations can reduce tremors as well as limiting nicotine and caffeine intake.

Cognitive dysfunction:

Mental dullness or lack of mental creativity have been reported alongside negative effects on verbal learning and memory domains.

However, many cognitive dysfunctions are associated with bipolar disorder itself and can be associated with other medications such as antipsychotics, SSRIs, and benzodiazepines. [11]

Endocrine side-effects:

Lithium can affect the thyroid and parathyroid glands.

Lithium reduces thyroxine secretion leading to an increase in TSH and the associated clinical picture of hypothyroidism resulting in lethargy, depression, weight gain, and dry skin.

Clinically significant hypothyroidism occurs in 8-19% of patients on lithium compared to 0.5-1% of the general population. Women and elderly are particularly prone. [12]

Lithium is associated with hyperparathyroidism which leads to hypercalcaemia.

Renal side-effects :

Frequent urination (polyuria) and excessive thirst (polydipsia) are consistently reported during the initial stages of lithium therapy and are also likely to be related to each other (i.e. thirst is secondary to renal-mediated polyuria).

It is caused by lithium inhibiting the action of antidiuretic hormone (ADH).

The decreased ability of the kidney to concentrate urine predisposes patients to diabetes insipidus which affects approximately 10% of lithium-treated patients. This can be moderated by amiloride and potentially by the carbonic anhydrase inhibitor acetazolamide.

Lithium levels > 0.8 mmol/L are associated with a higher risk of renal toxicity.

End-stage renal failure occurs in 0.53% of lithium-treated patients compared to 0.2% of the general population.

512 bipolar patients followed up showed that lithium tended to begin to decrease estimated GFR (eGFR) after 10–15 years and risk of low values typically required 30 years of treatment, although no patient went on to end-stage renal failure requiring dialysis. The following are risk factors for low eGFR: [13]

• Longer lithium treatment
• Lower lithium dose
• Higher serum lithium concentration
• Older age (starting lithium at age ⩾40 years)
• Medical comorbidity
• Low initial baseline eGFR.

Metabolic side-effects

Calabrese reported that mean weight change over one year in a double-blind study of lithium-treated patients was 4.2 kg. [14]

However, for the majority of bipolar patients weight gain is more likely to occur due to other psychotropic medications (such as antipsychotics, valproate and some antidepressants).

It is important to understand lithium’s mechanism of action and to determine the effect a patient’s age, body composition, and disease states has on the clinical outcome, side-effects, and potential toxicities.

Bringing these clinical insights together along with awareness of significant drug interactions can aid in optimising lithium management.

The RANZCP mood disorder guidelines recommend the following timetable for monitoring of side effects.

LITHIUM TOXICITY

Acute toxicity:

At levels above 1.5, mmol/L gastrointestinal (increasing nausea, anorexia, diarrhoea) and CNS effects ( muscle weakness, drowsiness, ataxia, coarse tremor and muscle twitching) occur.

Above levels of 2.0, mmol/L increasing disorientation and seizures can occur.

However, in some instances, even such high plasma levels may lead to mild symptoms.

Chronic toxicity:

Because lithium has a longer half-life in brain tissue than in plasma, long-term lithium treatment can lead to lithium accumulation in the brain and lead to chronic toxicity.

Haemodialysis can treat lithium toxicity. Potassium (20-50 mmol/day) is also useful in reducing the effects of lithium toxicity on the kidney. N-acetyl cysteine may prevent lithium-induced renal damage. [8]

DRUG INTERACTIONS

Many patients taking lithium will also be taking it in combination with anticonvulsants, antipsychotics, or antidepressants.

It is important to note any clinically relevant drug interactions:

Carbamazepine:

Enhances the neurological effects of lithium including dizziness, tremors, confusion, and hyperreflexia. This can occur even in the absence of detectable serum increases

NSAIDs:

Lithium clearance is reduced with lithium levels increasing from 10% – greater than 4 fold increases.

Thiazide diuretics:

Thiazide diuretics can dramatically increase lithium serum levels (up to 4 fold increases).

Iodides: 

Such as potassium iodide increase the hypothyroid properties of lithium whereby it decreases the release of thyroid hormone from the thyroid gland

Antidepressants:

Lithium increases serotonergic side effects and therefore increases the risk of the patient developing serotonin syndrome

ACE Inhibitors:

Increase sodium and water excretion rates thus actively retaining lithium. Therefore, the increase in lithium serum levels can cause toxicity (up to 4 fold increases).

CLINICAL USE OF LITHIUM

Initiating:

The recommendation is to commence therapy with a low and divided dose and to increase this until a serum lithium level of 1.2 mmol/L is reached. Patient requires monitoring and assessment for adverse events as the dose is increased closer to the therapeutic range.

Lithium naive patients should have lithium levels of 0.8 – 1.0 mmol/L.

The NICE guidelines propose a starting level of 0.6 -0.8 mmol/L.

The APA proposes a higher level of 0.8-1.0 mmol/L for controlling symptoms but low levels of 0.4-0.6 mmol/L for prophylaxis long term.

Tailoring:

For prophylaxis, a lower dose of 0.4-0.6 mmol/L may be sufficient whereas for stabilizing patients, it is recommended that a serum concentration of 0.6-0.8 mmol/L may be required.

For the control of mania, a serum concentration of 0.8-0.1 mmol/L is more common.

Maintenance:

In clinical practice, the serum concentration of lithium requires the clinician to understand the risk-benefit ratio of lithium maintenance therapy.

Low serum levels (0.4-0.6 mmol/L) may not be as efficacious as a higher serum level (0.8-1.1 mmol/L) however dropout rates are greater due to tolerability issues at this higher serum level.

Patients likely to have depressive episodes may benefit from prophylactic levels of 0.4-0.8 mmol/L, whereas in those more likely to have mania, levels of 0.6 – 1.0 mmol/L may be more effective.

Long-term:

The long-term maintenance of the recommended target plasma lithium level provides effective prophylaxis and the prevention of symptom recurrence.

Adherence rates are often impaired due to weight gain, polyuria, tremor, and fatigue.

Psychoeducation for the patient and their supportive network is crucial as is careful and frequent monitoring of the patient to ensure compliance is maintained.

Below are the serum levels for initiation and prophylaxis based on different guidelines.

A joint International Society for Bipolar Disorders (ISBD) and International Study Group on Lithium (IGSLI) consensus suggested :

For adults with bipolar disorder:

• 0.60‐0.80 mmol/L with the option to reduce it to 0.40‐0.60 mmol/L in case of good response but poor tolerance or to increase it to 0.80‐1.00 mmol/L in case of insufficient response and good tolerance. [Nolen W et al., 2019]

LITHIUM OROTATE

Lithium orotate (LiC₅H₃N₂O₄) was initially advocated by Hans Nieper in the 1970s, who proposed that orotic acid was a superior carrier compound that could more readily transport inorganic ions across biological membranes.

Lithium orotate (LO) was found to have greater lithium brain levels than lithium carbonate at equivalent concentrations, thus offering the potential to maintain a lower lithium dose. [Pacholko & Bekar, 2021]

LO fell out of favour due to a greater incidence of renal impairment compared to Lithium carbonate.

LO is available over the counter as a nutraceutical.

Benefits: 

• Increased brain lithium concentrations relative to lithium carbonate at equivalent concentrations
• potential for lower toxicity due to lowered dose requirements
• Potential for greater compliance due to better side effect profile

Disadvantages: 

• Potential greater renal toxicity
• Unknown therapeutic window
• No dosage guidelines
• Lack of randomised clinical trials

The usual dose of LO is 120 mg daily (equivalent to 5 mg of elemental Lithium) [250 mg of Lithium carbonate = 50 mg of elemental Lithium)

Further research is required to support the use of LO in clinical practice; however, clinicians need to be aware of the use of LO in alternative medicine.

Read more about Nutraceuticals in Psychiatry. 

CONCLUSION

Lithium is considered a gold-standard treatment for bipolar disorders and a first-line mood stabiliser in many clinical guidelines.

It is important that clinicians appreciate the pharmacokinetics and pharmacodynamics of lithium to ensure the greatest efficacy in the absence of overt toxicity.

The utilisation of treatment guidelines, in conjunction with a clinician’s experience, should guide an appropriate and relevant treatment strategy for bipolar disorder that is tailored to the individual.

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