• Discuss the possible mechanisms of action of lithium.

Lithium inhibits several enzymes involved in the recycling of neuronal membrane phospholipids. This results in the depletion of 2^nd messengers (PIP2, IP3 and DAG). It also inhibits glycogen synthase kinase-3.

• What is the therapeutic index of lithium and what is its clinical significance?

Its target plasma concentration levels are between 0.6 and 1.4mEq/L. Its clinical significance is for the treatment of bipolar disorder, recurrent depression and schizoaffective disorder.

• When is lithium used as single drug and in which cases and with which type of drugs is lithium combined?

Lithium is used as monotherapy for bipolar disorder and acute manic episodes and rapid cycling. Lithium should be used in combination with antidepressants or benzodiazepines for severe depressant episodes. The initial treatment with SSRI can cause manic episode. Lithium and valproate may be used in combination when there is no or partial response to lithium monotherapy.

• Name 3 clinically significant interactions lithium may have with other drugs. Illustrate your answer with suitable examples of drugs.

Interaction with diuretics (thiazides), NSAID’s (ibuprofen), ACE Inhibitors and fluoxetine – increase lithium levels that may be toxic.

Interaction with typical anti-psychotic drugs (chlorpromazine) lead to increased severity of EPS.

Interaction with anti-convulsants (carbamazepine), calcium channel blockers (amlodipine) and anti-histamines (losartan) may lead to lithium toxicity.

• Name the major side effects of lithium.

Tremors, sedation, ataxia, aphasia, muscle weakness, fatigue, polydipsia, polyuria, nocturia, nephrogenic diabetes insipidus, thyroid enlargement, leucocytosis, oedema, acne, alopecia, sexual dysfunction and bradycardia-tachycardia.

• What is the status of the use of lithium during pregnancy and lactation?

Category D: evidence that it causes fetal birth defects.

• Name three other important indications for lithium.

Depression, mania and schizophrenia.

Evaluate the following case and fully motivate your recommendations:

Ms B. Polar (21 years, 60 kg) is a student and used the following medication for the past two months:

Camcolith 600mg bd. The plasma levels after two weeks were 0.8mmol/l. She sustained a muscle injury and has been using Indocid® 75mg nocte for the past 10 days. On questioning she reveals that “she had picked up a lot of weight” and is now using some of her mother’s “water pills” in the hope of losing a few of the extra kilos. However, she complains of fatigue, that she has difficulty in keeping her eyes open in class, remains thirsty and constantly feels shaky and nauseous.

Camcolith is a form of slow-release lithium. There is an interaction between the lithium and the NSAID and lithium and the diuretic (water pill), that increases lithium plasma level and could lead to lithium toxicity. This could be the result of her dehydration (excessive thirst), fatigue and sedation (struggle to keep eyes open), weight gain and tremors. The recommendation would be to immediately stop the use of the NSAID and the diuretic. Because she is still so young, it would be advisable for her to switch over to fluoxetine.