Lithium is a monovalent cation which belongs to the group of alkali metals together with sodium, potassium and other elements with which it shares some of its properties.

The mechanism whereby lithium controls manic episodes and possibly influences affective disorders is not yet known.

Unlike other antimanic agents, it does not possess general sedative properties. There is evidence, however, that lithium alters sodium transport and may interfere with ion exchange mechanisms and nerve conduction. Fluid and electrolyte metabolism are believed to be altered in affective disorders and this may be related to the therapeutic action of lithium. Lithium enhances the uptake of norepinephrine and serotonin into the synaptosomes, thus reducing their action. It reduces release of norepinephrine from synaptic vesicles and inhibits production of cyclic AMP.

Lithium is inactive in most screening psychopharmacological tests but it produces marked potentiation of amphetamine hyperactivity in animals. It does not appear to protect against the action of stimulant and convulsive drugs and produces only slight potentiation of CNS depressants.

Lithium can replace sodium in extracellular fluid and during the process of depolarization it has an extremely rapid intracellular influx. However, it is not effectively removed by the sodium pump, thereby preventing the cellular reentry of potassium. As a result, it interferes with electrolyte distribution across the neuronal membrane, leading to a fall in membrane potential and changes in conduction and neuronal excitability. In humans, lithium alters the excitability of the CNS as measured by cortical evoked potentials.

Balance studies indicate that lithium may produce a transitory diuresis with increase in sodium and potassium excretion. A period of equilibrium or slight retention may follow but persistent polyuria may occur in some patients. There is evidence that therapeutic doses of lithium decrease the 24-hour exchangeable sodium. Longitudinal metabolic studies have demonstrated cumulative lithium retention in some patients without undue rise in plasma lithium values, indicating a possible intracellular retention of lithium. There is some evidence that lithium may affect the metabolism of potassium, magnesium and calcium.

ECG changes with lithium have been reported in man.

The primary toxic effects in man appear to be on the central nervous system.

The therapeutic dose for the treatment of acute mania should be based primarily on the patient's clinical condition. It must be individualized for each patient according to blood concentrations and clinical response. For manic patients, the dosage should be adjusted to obtain serum concentrations between 0.8 and 1.2 mmol/L (in blood samples drawn before the patient has had his first lithium dose of the day). ....

Lithium toxicity is closely related to the concentration of lithium in the blood and is usually associated with serum concentrations in excess of 2 mmol/L. Early signs of toxicity which may occur at lower serum concentrations were described under Adverse Effects and usually respond to reduction of dosage. Lithium intoxication has been preceded by the appearance or aggravation of the following symptoms: sluggishness, drowsiness, lethargy, coarse hand tremor or muscle twitchings, loss of appetite, vomiting, and diarrhea. Occurrence of these symptoms requires immediate cessation of medication and careful clinical reassessment and management. Signs and symptoms of lithium intoxication have already been described under Adverse Effects.

The best source of information on bipolar is "Manic Depressive Illness" by Goodwin and Jamison, Oxford University Press, 1990 (1,000 pages; a medical textbook with very up to date information). Below are some excerpts

Lithium affects all parts of the body, but three targets are the most important: thyroid, kidney, and CNS (central nervous system), especially WHEN TREATMENT EXTENDS OVER A LONG PERIOD:

Hypothyroidism in 5-35% of patients; apparantly dose related Nontoxic goiter in 4-12%

Tubular function impairment--related to dose and duration of treatment: Decreased renal concentrating ability in 15-30% Polyuria [24 hr urine volume greater than 3 liters] in 50% initially; persists in 20-40% on long term maintenance Histological abnormalities (15%): interstitial fibrosis, tubular atrophy, sclerotic glomeruli No association (as of 1990) has been found between lithium administration and renal failure or terminal azotemia requiring dialysis, even in patients continually on the drug for 20 years or more. However, in the case of lithium overdose where plasma level is greater than or equal to 3 mmol/liter and/or the patient is comatose, in shock, or severely dehydrated renal hemodialysis (or peritoneal dialysis) should be started. In these situations, some permanent damage may occur.)

Usually transient effects Fine tremor in 33-65% of patients--more frequent in males; persists in 4-50% of patients in maintenance Decreased motor coordination Muscular weakness Extra pyramidal Cogwheel rigidity in 48-59% of patients--assocated with longer treatment Nonspecific EEG changes Cognitive (intellectual functioning, creativity) and memory impairment

Transient, related to rapid dose increase and timing of dose In all cases, keeping patients at the lowest effect doseage prevents many of these, although any of these may occur over a longer term.