Lithium



Lithium is used as a psychiatric treatment
against the recurrence of mania
and as a treatment, and prophylaxis for, depressive disorders.

Lithium may have some antidepressant effects
but these are less than those of less-toxic agents such as tricyclics.

Lithium-enhanced use of high dose tricyclics
is a treatment alternative for depressive illness where the use of high dose tricyclics alone
has failed to have a therapeutic effect (see notes).

Notes:
dosulepin, phenelzine, combined antidepressants,
and lithium augmentation of antidepressants
should only be routinely initiated by specialist mental health professionals,
including General Practitioners with a Special Interest in Mental Health (1)

Reference:
NICE (December 2004).Depression Management of depression in primary and secondary care

Pharmacology



Lithium ions
- displace sodium and potassium from body fluids,
- substitute for sodium in nerves and muscles,
- and interfere with calcium and magnesium metabolism.
- They probably affect membrane transport,
- and have diverse effects on central transmitter systems.

The drug accumulates in body fluids,
and rates of excretion depend on individual renal clearance
and are lower in old age.

In patients with normal renal function,
the elimination half-life of lithium is about 20-24 hours.

Steady state concentrations are reached about 5 days after starting the drug (1).

There is a specific effect of lithium on the inositol triphosphate messenger system of cells,
but its significance is still uncertain.

Reference:

Drug and Therapeutics Bulletin, 37 (3), 22-24.

Pharmacokinetics/interactions



Elimination half-life of lithium, in patients with a normal renal function, is about 20-24 hours.
Steady-state concentrations are reached about 5 days after commencing the drug.

The glomerular membrane freely filters lithium, which is then reabsorbed in the proximal tubules
with, and to the same extent as, water and sodium.

Lithium clearance falls when the sodium plasma concentration is low, or the patient is dehydrated.

Serum lithium concentrations are likely to be raised in a patient
who has vomiting, diarrhoea, or excessive sweating,
a patient on a low-salt diet,
or a patient on a drug which reduces excretion of lithium
e.g. NSAID, diuretic, ACE inhibitor.
Reference:

Drug and Therapeutics Bulletin 1999; 37 (3): 22-24.

Indications



1. Mania:
In the acute phase as prophylaxis for mania

2. lithium-augmentation of antidepressants:
lithium may be administered with tricyclic depressants in cases of resistant depression
Failure to respond to lithium-augmented anti- depressants is an indication for ECT

3. Prophylaxis in depression:
lithium is less effective in preventing recurrences of depression
than in preventing episodes of bipolar affective disorder
Maintenance therapy with a first-line antidepressant drug is usually preferable

4. lithium has been used in the treatment of premenstrual tension

LITHIUM CONTRAINDICATIONS


Lithium should be used with caution in patients with the following conditions:
- renal disease
- thyroid disease
- heart disease
- epilepsy
- organic brain damage

Lithium should be avoided during pregnancy
as there is an increased risk of foetal malformations.


LITHIUM AND DRUG INTERACTIONS


The most important drug interaction of lithium
is with sodium depleting drugs especially thiazides where significant lithium toxicity may occur.
Other drugs such as NSAIDs, phenothiazines, carbamazepine, and phenytoin can also increase toxicity.
LITHIUM TREATMENT REGIME

The treatment regime is adjusted for each patient according to blood levels and side effects.
Renal and thyroid function should be assessed before starting the first week of treatment with lithium carbonate.
Subsequent doses depend on the blood levels.

As a prophylactic, blood levels of 0.4 to 0.8 mmol per litre may be continued for months or years
provided there are regular lithium estimations.

Blood levels of lithium should be measured weekly until a steady-state is reached.
Thereafter, estimations may be less frequent e.g. 6-12 weekly.

Blood for lithium estimation should be taken 12 hr after the last dose.

Thyroid function should be checked every 6 months.




A delayed release preparation (Priadel) is available though its pharmokinetics are similar to those of lithium carbonate.

Lithium is normally given in divided doses (at least twice daily) to reduce peak levels in glomerular filtrate.

LITHIUM Adverse effects



Adverse effects are not uncommon even if blood levels are carefully controlled,
and patients must be supervised.

Common side effects within the therapeutic range include


- hand tremor,
- muscular weakness,
- nausea,
- polydipsia, and polyuria.

These are not usually dangerous,
but may indicate the beginning of the toxic syndrome.

Tremor is very common.
Thyroid enlargement,
hypothyroidism,
ECG changes,
a diabetes insipidus-like syndrome
and depletion of calcium from bone
may also take place.

The patient may complain of a metallic taste in the mouth due to lithium treatment.
Skin rashes may occur.

The toxic syndrome occurs at levels above 1.4 mmol/l,

and involves
diarrhoea, vomiting,
ataxia, nystagmus,
dysarthria,
confusion,
epileptic seizures,
which may lead to coma with hypereflexia
and increased muscle tone
- and in a few patients to irreversible neurological damage.

If this syndrome occurs then the lithium salts should be discontinued,
the fluid and electrolyte balance corrected,
forced diuresis or dialysis,
and symptomatic and supportive measures given, e.g. for seizures (1).

Note that there are certain circumstances
where the patient is particulary at risk of developing a toxic reaction,
these include:
- impaired renal function
- dehydration, for example due to diarrhoea and vomiting,
- or increased perspiration when visiting a hot climate.

If the patient becomes - - dehydrated lithium treatment should be stopped.

The most important drug interaction of lithium is with sodium depleting drugs
especially thiazides where significant lithium toxicity may occur.
Other drugs which reduce lithium excretion include ACE inhibitors and NSAIDs (1).

Reference:

Drug and Therapeutics Bulletin (1999), 37 (3), 22-24.

Lithium monitoring/starting treatment



Time to steady state - it takes four to five days for a steady state to occur after commencement of lithium
(lithium carbonate or lithium citrate) therapy.
At this time the first sample should be taken after starting treatment.

Therapeutic range (may vary with respect to different laboratories and therapeutic indication):

once daily dose - at 12 hours, 0.7 to 1.0 mmol/l; at 24 hours, 0.4 to 0.8 mmol/l
twice daily dose - at 12 hours, 0.4 to 0.8 mmol/l
Notes:

NICE state that (2)
serum lithium levels should be checked 1 week after starting and 1 week after every dose change, and until the levels are stable.
The aim should be to maintain serum lithium levels between 0.6 and 0.8 mmol per litre in people being prescribed it for the first time
for people who have relapsed previously while taking lithium or who still have sub-threshold symptoms with functional impairment while receiving lithium, a trial of at least 6 months with serum lithium levels between 0.8 and 1.0 mmol per litre should be considered
Reference:

Drug and Therapeutics Bulletin 1999; 37 (3): 22-24.
NICE (July 2006). Bipolar Depression.
NICE (September 2014). Bipolar disorder: the assessment and management of bipolar disorder in adults, children and young people in primary and secondary care

Lithium (stopping treatment)



Abrupt withdrawal of lithium treatment in a patient with bipolar disorder
increases the risk of recurrence of a major episode of illness

lithium treatment should be gradually discontinued over at least 4 weeks
to reduce the risk
(and preferably over a period of up to 3 months, particularly if the patient has a history of manic relapse
(even if they have been started on another antimanic agent) (2))
during dose reduction and for 3 months after lithium treatment is stopped,
Monitor the person closely for early signs of mania and depression

If a patient is to have a major operation

, it is wise to stop lithium treatment for 24 hours before the operation;
provided serum electrolytes are normal. Lithium treatment should usually be restarted soon after the operation (1)
discontinuation of lithium prophylaxis should be discussed between GP, specialist and patient
Notes:

when lithium treatment is stopped or is about to be stopped abruptly, prescribers should consider changing to monotherapy with an atypical antipsychotic or valproate, and then monitor closely for early signs of mania and depression
Reference:

Drug and Therapeutics Bulletin 1999; 37 (3): 22-24.
NICE (April 2018). Bipolar Disorder.

Before commencing lithium treatment



Measure:
- thyroid function - management of any hypothyroidism should be addressed before starting lithium.

- renal function - a sufficient guide to renal function is provided by serum creatinine.
If serum creatinine is abnormal
then measurement of creatinine clearance may be required.
A lower dose of lithium will be required if there is evidence of renal impairment.

ECG - recommended by some specialists if there is a history of cardiac abnormality.



With respect to lithium treatment in women:
lithium treatment should be avoided during the first trimester.
reliable contraception should be used by women of child- bearing age.
Reference:

Drug and Therapeutics Bulletin 1999; 37 (3): 22-24.

Acute lithium toxicity



The toxic syndrome occurs at levels above 1.4 mmol/l
and involves

1. GASTROENTEROLOGICAL SYMPTOMS AND SIGNS
a decreased appetite,
diarrhoea, vomiting,

2. NUROLOGICAL SYMPTOMS AND SIGNS
ataxia,
nystagmus,
dysarthria,
confusion,
and epileptic seizures.
Toxicity may lead to coma with hypereflexia and increased muscle tone.
A few patients may sustain irreversible neurological damage.

3. CARDIOTOXICITY

AV heart block can occur in lithium toxicity (1)
although first-degree block is seen more frequently,
complete AV block can occur in lithium cardiotoxicity
If this syndrome occurs then the lithium salts should be discontinued.

Treatment of lithium toxicity

is supportive with special regard to
- electrolyte balance,
- renal function
- and control of convulsions

seek expert advice
whole bowel irrigation should be considered for significant ingestion,
but advice should be sort from a poisons information centre

In acute overdose situations with no clinical manifestations,
methods to increase urine production such as ensuring adequate fluid intake may be sufficient,
but diuretics should be avoided

Raising urine pH may have a limited effect on increasing lithium excretion
if there is renal failure or if the above
fail to improve the clinical condition and reduce plasma lithium levels,
haemodialysis may be needed
benzodiazepines may be required for agitation
Notes:

There are certain circumstances where the patient is particulary at risk of developing a toxic reaction:
impaired renal function
dehydration - due to, for example, diarrhoea and vomiting,
or increased perspiration when visiting a hot country.
If the patient becomes dehydrated lithium treatment should be stopped

Significant lithium toxicity may occur when lithium is allowed to interact with sodium depleting drugs especially diuretics
There is evidence that in older persons, the use of loop diuretics or angiotensin converting enzyme inhibitors
increased the risk of hospital admission for lithium toxicity.
This is especially during the initial month of treatment (2)

Severity of toxicity (3):
in 1978, Hansen and Amdisen proposed a classification for the severity of lithium intoxication based on serum lithium concentration
subdivided their investigational cohort into those who were mildly intoxicated (1.5-2.5 mmol/L), those who were seriously toxic (2.5-3.5 mmol/L), and those who were suffering from life-threatening toxicity (>3.5 mmol/L)
authors concluded that no "clear-cut relationship" exists between the serum lithium level and the severity of symptoms



Reference:

Serinken M et al. Rarely seen cardiotoxicity of lithium overdose: Complete heart block. International Journal of Cardiology 2009; 132 (2): 276-278.
Juurlink DN et al. Drug-induced lithium toxicity in the elderly: a population-based study. J Am Geriatr Soc 2004;52: 794-8
H.E. Hansen, Amdisen. A. Lithium intoxication. Q J Med 1978;47: 123-144.