- It increases adenylate cyclase activity, and inositol monophosphatase. This affects the PI signalling pathway (PI = phosphoinositide). The result of this is a stablising effect on aminergic and cholinergic activity. This results in stabilised intracellular signalling pathways – the pathways have increased basal activity – but respond less strongly to stimuli.
- Suppression of apoptosis genes (glucose synthase kinase – GSK-3) and enhanced expression of anti-apoptosis genes. This results in neuroprotection.
- Increased neurogenesis.
- It is given as a salt – e.g. carbonate or citrate. This is absorbed very quickly – which can be problematic as this can cause excessively high plasma concentrations in the short term. To get around this, it is usually given in modified release formulas.
- It has an unusual pattern of excretion – whereby about ½ is excreted within 12 hours, but the other half takes 1-2 weeks to be removed (presumably because it is all stored in peripheral tissues). This means that you have to monitor doses very carefully.
- it gets concentrated in bone and in the thyroid
- excreted by the kidney – in the golomerulus – but then, like Na+, it is reabsorbed in the proximal tubule (~80%)
- when the body has low salt and water concentrations, then excess lithium re-absorption can occur – resulting in acute toxicity.
- Lithium has a very narrow therapeutic index
- Regular monitoring of plasma levels is required in patients receiving lithium – in long term treatment this needs to be done at least every 3 months. The dose is adjusted according to the plasma concentration.
- Nausea vomiting and diarrhoea – see above – wary of toxicity
- CNS effects – Tremor, ataxia, dysarthria, ‘giddiness’
- Polyuria resulting in excess thirst – due to inhibition of ADH/reduced tubular responsiveness to ADH – DIABETES INSIPIDUS
- In long term use serious renal tubular damage can occur.
- Thyroid enlargement and hypothyroidism
- Weight gain
- Toxic effects – confusion, motor impairment, coma, convulsions, hypotension, oliguria
- Drug interactions – treatment with diuretics can reduced lithium excretion, and may cause toxicity. The effect is worst with the thiazides – because they have a long duration of action.
- ACE-i’s and NSAID’s can also reduce the excretion of lithium
- There is an increased risk of extrapyramidal effects if these are given in conjunction with an antipsychotic.
Uses of mood stabilisers
- When given acutely they are only likely to reduce mania, and have little effect on depression – although lithium may be used adjunctively in severe depression.
- Antipsychotics are more likely to be given in acute mania – as they are safer and act more quickly.
Mania – used in both prophylaxis and treatment
These drugs have a modulating effect on GABAergic neurons.