Lithium

Question 1

Take a focused history for someone on lithium presenting with complaining of poor sleep, feeling tired and weakness in his arms. His family reported that he has been irritable, and that he is losing weight

Answer 1

1. take a focussed history using systemic approach;
2. eliciting relevant history of experience with lithium including side effects, toxicity, adherence,
3. medical history; prioritising the range of hyperthyroidism /hypothyroidism symptoms;
4. screening questions relating to other physical systems – GIT, CVS, RS and CNS;
5. clarifying important positive and negative features;
6. clarifying timeframes;
7. establishing symptom effect on function.

Question 2

Three major drug classes identified as potential precipitants of lithium toxicity:

Answer 2

Diuretics that promote renal sodium excretion;

The antihypertensive class of angiotensin II receptor antagonist, which reduce glomerular perfusion pressure and can enhance the tubular reabsorption of lithium;

Nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit renal prostaglandin synthesis.

Question 3

Lithium pharmakokinetics

Answer 3

Almost completely absorbed from GIT within 8 hours
Peak concentrations in 2-4
VD determined by total body water
Elimination via the kidneys
Crosses the placenta, breast milk and CSF
Half life 18-24 hours (longer in elderly)
Not metabolised or protein bound
Excretion linked with sodium excretion
Lithium inhibits own clearance, therefore clearance declines with ++serum levels

Question 4

Short term effects of lithium therapy

Answer 4

fine tremor, mild gastrointestinal upset (especially nausea, diarrhoea), ankle oedema, increased thirst and urination

fatigue, general slowing (or cognitive blunting) of thought processes and poor concentration.

There is a dose-response relationship between the severity of GI symptoms and plasma Lithium: keeping to the recommended 0.5–0.8 mmol/L helps to minimise symptoms

Question 5

Tremor in therapeutic treatment vs toxicity

Answer 5

Fine tremor when therapeutic, course tremor in toxicity

Question 6

Medium to long-term effects of lithium

Answer 6

neuroendocrine changes, hypo- and hyperthyroidism and hyperparathyroidism.

Lithium causes two types of renal toxicity – decreased renal concentrating ability and chronic renal failure.
Nephrogenic diabetes insipidus is observed in 40–50% of patients.
Chronic renal failure is observed in patients treated for more than 7–20 years

Question 7

Lithium and the thyroid gland

Answer 7

Lithium is taken up into the thyroid gland and accumulates there at high concentrations

The effects of lithium do not appear to be dose dependent or related to the length of treatment with lithium.

Uptake into the thyroid gland occurs from the first administration, but not all patients develop thyroid disorders.

Question 8

Sx of hyperthyroidism

Answer 8

Loss of weight despite adequate diet, difficulty swallowing, heat intolerance, sweating, diarrhoea, tremor, irritability, proximal muscle weakness, palpitations, emotional lability, difficulty sleeping, psychosis, itch, reduced libido, sexual dysfunction and infertility.

Thyroid associated ophthalmopathy (grittiness, increased tear production, swelling, visual loss, double vision).

Question 9

Lithium toxicity

Answer 9

Relatively rare, life threatening
neurological, renal and cardiac compromise
Can occur at therapeutic doses after long period of treatment

Risks:
Changes in sodium level/way in body handles sodium (drugs, dehydration, physical illness-Addison’s, salt diets)

Nephrotoxicity main event in chronic setting

Question 10

Three patterns of lithium toxicity

Answer 10

1. Acute toxicity (poisonings in lithium naïve patients, in whom symptoms may be absent or minor, despite high serum lithium concentrations)
2. Acute-on-chronic toxicity (occur after acute lithium self-overdose in a previously lithium-treated patients)
3. Chronic toxicity (occurs insidiously due to lithium accumulation in a chronically lithium-treated patients)

Question 11

Classification of lithium toxicity

Answer 11

Grade 1- mild:
GIT: nausea, vomiting,
Neurological: tremor,
Motor: hyperreflexia, agitation, muscle, weakness and ataxia

Grade 2- moderate:
Neurological: stupor,
Motor: muscular hypertonicity, rigidity,
Other: hypotension

Grade 3- severe:
Neurological: altered mental status, convulsions,
`Motor: myoclonus, collapse

Question 12

Lithium levels

Answer 12

Prophylaxis 0.4-0.6 mmol/L
Mania 0.8-1.2mmol/L
Toxicity >1.2 mmol/L

Question 13

Drug interactions

Answer 13

It takes few days to several weeks to develop signs of toxicity.

1. Angiotensin converting enzyme inhibitors (ACE inhibitors – captopril, enalapril, lisinopril, perindopril, ramipril etc),
2. Thiazide diuretics (Bendroflumethiazide, indapamide etc),
3. NSAIDs (or COX 2 inhibitors) – diclofenac, celecoxib, ibuprofen, indomethacin, meloxicam, naproxen etc., cause clinically relevant drug interactions.
4. Other
   - carbamazepine

Care is also required with angiotensin II receptor antagonist and SSRIs.

Question 14

Mortality rate in lithium toxicity

Answer 14

Severe lithium toxicity may result in a mortality rate of up to 15%, and a 10% rate of neurological sequelae

Question 15

Indications for lithium

Answer 15

1. Acute treatment mania
2. Treatment of acute mani already on long term lithium
3. Maintenance treatment BPAD
4. Augmentation in unipolar depression
5. Prophylaxis unipolar depression
6. Other
   - raise WCC in those with clozapine
   - self mutiliating/suicidal behaviour
   - prevent and treat steroid induced psychosis

Question 16

Pre-treatment workup

Answer 16

eGFR- renal toxicity
TFTs- hypo/hyperthyroidism
Calcium- hyperparathyriodism
ECG-minor ST changes maybe seen in toxicity
Wt

Question 17

Starting lithium

Answer 17

Start 400mg at night (200mg in the elderly)
Plasma level after 7 days
Then pLasma level 7 days after every dose change until desired level is reached
Bloods taken 12 hours after last dose
With liquid, clearly specific strength required

Question 18

Monitoring

Answer 18

Plasma lithium every 6 months (more freq if drug interactions)
eGFR, TFTs every 6 months
Wt and calcium also monitored

Question 19

Stopping lithium

Answer 19

Reduce slowly over at least 1 month

Avoid incremental reductions of lithium levels of more than 0.2mmol/L

Question 20

Important reference for lithium and suicide

Answer 20

“Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis”
Cipriani et al- 2013
Lithium is an effective treatment for reducing the risk of suicide in people with mood disorders.

Lithium may exert its antisuicidal effects by reducing relapse of mood disorder, but additional mechanisms should also be considered because there is some evidence that lithium decreases aggression and possibly impulsivity, which might be another mechanism mediating the antisuicidal effect.

Cipriani et al- BMJ 2013
Estimated that 15% of people with BPAD take their own life. A MA of clinical trials concluded that Lithium reduced by 80% the risk of both attempted and completed suicide in patients with BPAD.

Large data based studies have shown that lithium treated pts are less likely to complete suicide than patients treated with other mood stabilising drugs.

Question 21

Suicide rate in BPAD

Answer 21

15x rate of those without BPAD

15%

Question 22

BALANCE study

Answer 22

Lithium. The BALANCE study Geddes et al 2002, World psychiatry
demonstrated that lithium alone and in combination with valproate is effective in prophylaxis. Lithium is more effective alone than valproate alone, and carries the extra significant benefit of reducing suicidal behaviour and death by suicide

Question 23

Differential diagnosis presumptive lithium toxicity

Answer 23

1. Serotonin syndrome (SS)-> +temp, fever can also precipitate lithium toxicty
2. neuroleptic malignant syndrome (NMS)-> lead pipe rigidity

Ultimately, a serum lithium concentration helps to confirm the diagnosis of lithium poisoning.

3. acute ethanol or benzodiazepine withdrawal. Signs and symptoms can include tachycardia, hypertension, hyperthermia, agitation, and possibly seizures and hallucinations. Neuromuscular findings are more prominent with lithium poisoning and less commonly seen with either ethanol or benzodiazepine withdrawal.
4. Hypoglycemia
5. Central nervous system infection
6. Head trauma
7. Stroke
8. Seizures and status epilepticus
9. Drug intoxication (anticholinergic, phencyclidine, cocaine)
10. Myxedema coma or thyrotoxicosis