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Mood Stabilisers e.g. lithium, valproate, gabapentin, carbamazepine
Mood stabilisers are mainly used to treat bipolar disorder although they may be used in lots of other psychiatric conditions.
Lithium
Lithium has a narrow therapeutic window, as it quickly becomes toxic as levels increase.
It exists in a cationic state, and is able to replace Na+ in many reactions – e.g. it can enter cells via voltage gated Na+ channels. It does not replace Na+ in the sodium/potassium pump however, and this means that it accumulates inside cells.
Mechanism
This is very poorly understood. It is thought to interfere with lots of enzymes, and thus alter signal transduction pathways.
The main mechanisms are thought to be:
- 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.
Basically – there are complex alterations to intracellular signalling in neurons.
Pharmacokinetics
- 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.
Unwanted Effects
- 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
Bipolar Disorder – they can be used here as prophylaxis. They are usually given long term, but their beneficial effects take 3-4 weeks to develop.
- 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
Carbamazepine and valproic acid are generally used in the prophyalxis and treatment of mania when the patient is unresponsive to lithium. However, they are becoming more popular because they are safer and have fewer side effects.
These drugs have a modulating effect on GABAergic neurons.
These drugs have a modulating effect on GABAergic neurons.
