Lithium

The mode of action is not fully understood. The main effect of lithium is probably to inhibit hydrolysis of inositol phosphate, so reducing the recycling of free inositol for synthesis of phosphatidylino-

3 Cade J F. 1970 The story of lithium. In: Ayd F J, Blackwell B (eds) Biological psychiatry. Lippincott, Philadelphia.

sitides. These intracellular molecules are part of the transmembrane signalling system that is important in regulating intracellullar calcium ion concentration, which subsequently affects neurotransmitter release. Other putative mechanisms involve the cyclic AMP 'second messenger' system and mono-aminergic and cholinergic neurotransmitters.

Pharmacokinetics. Knowledge of pharmacokinetics of lithium is important for successful use since the therapeutic plasma concentration is close to the toxic concentration (low therapeutic index). Lithium is a small ion that, given orally, is rapidly absorbed throughout the gut. High peak plasma concentrations are avoided by using sustained-release formulations which deliver the peak plasma lithium concentrations in about 5 h. At first lithium is distributed throughout the extracellular water but with continued administration it enters the cells and is eventually distributed throughout the total body water with a somewhat higher concentration in brain, bones and thyroid gland. The apparent volume of distribution is about 50 1 in a 70 kg person (whose total body water is about 40 1) which is compatible with the above. Lithium is easily dialysable from the blood but the concentration gradient from cell to blood is not great and the intracellular concentration (which determines toxicity) falls slowly. Lithium enters cells about as readily as does sodium but does not leave as readily (mechanism uncertain). Being a metallic ion it is not metabolised, nor is it bound to plasma proteins.

Only the kidneys eliminate lithium. Like sodium, it is filtered by the glomerulus and 80% is reabsorbed by the proximal tubule but it is not reabsorbed by the distal tubule. Intake of sodium and water are the principal determinants of its elimination. In sodium deficiency lithium is retained in the body, thus concomitant use of a diuretic can reduce lithium clearance by as much as 50% and precipitate toxicity. Sodium chloride and water are used to treat lithium toxicity.

With chronic use the plasma t/2 of lithium is 15-30 h. Lithium is usually given 12-hourly to avoid unnecessary fluctuation (peak and trough concentrations) and maintain a plasma concentration just below the toxic level. A steady-state plasma concentration will be attained after about 5-6 days (i.e. 5 x t'/2) in patients with normal renal function. Old people and patients with impaired renal function will have a longer t|/2 so that steady state will be reached later and dose increments must be adjusted accordingly.

Indications and use. Lithium carbonate is effective treatment in > 75% of episodes of acute mania or hypomania. Because its therapeutic action takes 2-3 weeks to develop, lithium is generally used in combination with a benzodiazepine such as lorazepam or diazepam (or with an antipsychotic agent where there are also psychotic features).

For prophylaxis, lithium is indicated when there have been two episodes of mood disturbance in two years, although in some cases it is advisable to continue with prophylactic use after one severe episode. When an adequate dose of lithium is taken consistently, around 65% of patients achieve improved control of their illness.

Patients who start lithium only to discontinue it within two years have a significantly poorer outcome than matched patients who are not given any pharmacological prophylaxis. The existence of this 'rebound effect' dictates that persistence with long-term treatment is of great importance.

Lithium is also used to augment the action of antidepressants in treatment-resistant depression (see p. 375).

Pharmaceutics. It is important for any patient to adhere to the same pharmaceutical brand, as the dose of lithium ion (Li+) delivered by each tablet depends on the pharmaceutical preparation. For example, each Camcolit 250 mg tablet contains 6.8 mmol, each Liskonium 450 mg tablet contains 12.2 mmol and each Priadel 200 mg tablet contains 5.4 mmol of Li+. Thus the proprietary name must be stated on the prescription. Some patients cannot tolerate slow-release preparations because release of lithium ions distally in the intestine causes diarrhoea; they may be better served by the liquid preparation, lithium citrate, which is absorbed proximally. Patients who are naive to lithium should be started at the lowest dose of the preparation selected. Any change in preparation demands the same precautions as does initiation of therapy.

Monitoring. The difference between therapeutic and toxic doses is narrow and therapy must be guided by monitoring of the plasma concentration once a steady state is reached. Increments are made at weekly intervals until the concentration lies within the required range of 0.4-1 mmol/1 (maintenance at the lower level is preferred for elderly patients). The timing of blood sampling is important. By convention a blood sample is taken prior to the morning dose, as close as possible to 12 h after the evening dose. When the therapeutic range is reached, the plasma concentration should be checked every three months. Likewise, for toxicity monitoring, thyroid function (especially in women) and renal function (plasma creatinine and electrolytes) should be measured before initiation and every 3 months during therapy.

Patient education about the role of lithium in the prophylaxis of bipolar affective disorder and discussion of the pros and cons of taking the drug are particularly important to encourage compliance with therapy; treatment cards, information leaflets and where appropriate, video material are used.

Adverse effects. Lithium is associated with three categories of adverse effects.

• Those experienced at plasma concentrations within the therapeutic range (see above) include fine tremor (especially involving the fingers; if this is difficult to tolerate a (3-blocker may benefit), constipation, polyuria and polydipsia (due to loss of concentrating ability by the distal renal tubules), metallic taste in the mouth, weight gain, oedema, goitre, hypothyroidism, acne, rash, diabetes insipidus and cardiac arrhythmias. There can also be mild cognitive and memory impairment.

• Signs of intoxication, associated with plasma concentrations greater than 1.5 mmol/1 are mainly gastrointestinal (diarrhoea, anorexia, vomiting) and neurological (blurred vision, muscle weakness, drowsiness, sluggishness and coarse tremor, leading on to giddiness, ataxia and dysarthria).

• Frank toxicity, due to severe overdosage or rapid reduction in renal clearance, usually associated with plasma concentration greater than

2 mmol/1, constitutes an acute medical emergency. Hyperreflexia, hyperextension of limbs, convulsions, toxic psychoses, syncope, oliguria, coma and even death may result if treatment is not instigated urgently.

Overdose is treated by use of i.v. fluid to maintain a good urine output guided by frequent measurement of plasma electrolytes and osmolality. Hypernatremia indicates probable diabetes insipidus and isotonic dextrose should then be used until plasma sodium concentration and osmolality become normal. Isotonic saline forms part of the fluid regimen (but overuse may result in hypernatrae-mia) and potassium supplement will be required. Haemodialysis is effective but may have to be repeated frequently as plasma concentration rises after acute reduction (due to equilibration as lithium leaves cells and also by continued absorption from sustained-release formulations).

Interactions. Several types of drug interfere with lithium excretion by the renal tubules, causing the plasma concentration to rise. These include diuretics (thiazides more than loop type), ACE inhibitors and angiotensin-11 antagonists, and nonsteroidal anti-inflammatory analgesics. Theophylline and sodium-containing antacids reduce plasma lithium concentration. The effects can be important because lithium has such a low therapeutic ratio. Diltiazem, verapamil, carbamazepine and pheny-toin may cause neurotoxicity without affecting the plasma lithium. Concomitant use of thioridazine should be avoided as ventricular arrhythmias may result.

Carbamazepine

Carbamazepine is licenced as an alternative to lithium for prophylaxis of bipolar affective disorder, although clinical trial evidence is actually stronger to support its use in the treatment of acute mania. Carbamazepine appears to be more effective than lithium for rapidly cycling bipolar disorders, i.e. with recurrent swift transitions from mania to depression. It is also effective in combination with lithium. Its mode of action is thought to involve agonism of inhibitory GABA transmission at the GABA-benzodiazepine receptor complex (see also Epilepsy, p. 417).

Valproic acid

Valproic acid is the drug of first choice for prophylaxis of bipolar affective disorder in the United States, despite the lack of robust clinical trial evidence in support of this indication. But treatment with valproic acid is easy to initiate (especially compared to lithium), it is well tolerated and its use appears likely to extend if the evidence-base expands. As the semisodium salt, valproic acid is licenced for use in the treatment of acute mania unresponsive to lithium. (Note: sodium valproate, see p. 420, is unlicenced for this indication.)

Treatment with carbamazepine or valproic acid appears not to be associated with the 'rebound effect' of relapse into manic symptoms that may accompany early withdrawal of lithium therapy.

Other drugs

Evidence is emerging regarding the efficacy of lamotrigine in prophylaxis of bipolar affective disorder and treatment of bipolar depression. Other drugs which have been used in augmentation of existing agents include the anticonvulsant gabapentin, the benzodiazepine clonazepam, and the calcium channel blocking agents verapamil and nimodipine.

Drugs used ¡n anxiety and sleep disorders

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