Acute mania

Prevention of recurrent bipolar affective illness, especially manic episodes (not good for rapid cycling or mixed 

Other uses: recurrent depression, can be combined with antipsychotics to treat psychosis, unipolar depression who don't respond to antidepressants because they might actually be bipolar

Almost completely absorbed from GI tract (available in extended release tablet to prolong action) and distributed in extracellular fluid with gradual accumulation in various tissues to different degrees 

Final volume of distribution approaches that of body water

Lithium passes slowly through BBB so 40% CSF concentrations 

95% of single dose is eliminated in urine (t1/2 = 20-24 hours)

Repeated administration will increase half life to 2.4 days; also increases in geriatric patients and those with impaired renal function

Considerable pharmacokinetic variations with patients - can only be used safely in patients that can be regularly monitored 

.6 - 1.3 meq/L

Titration to higher doses should be done under very close supervision 

Avoid dehydration, this will up lithium concentrations

Excess sodium will enhance the elimination of sodium 

Excess sodium will enhance elimination of sodium

Decreased sodium will decrease the elimination of sodium 

Inhibits inositol monophosphatase

Inhibition of GPCRs

Inhibits growth factor pathways 

Lithium inhibits inositol monophosphatase -- which depletes IP3 and DAG formation 

Mania might be associated with a state of neuronal hyperactivity and thus lithium may selectively inhibit these pathways 

Lithium inhibits NE stimulated adenylate cyclase 

Major -- decreased ADH --> polyuria

Minor -- inhibition of TSH --> subclinical hypothyroidism 

Growth factors act through an enzyme called glycogen synthase kinase 3 to promote cell death 

Lithium inhibits this cell enzyme which can lead to neuroprotective effects and long term plasticity 

Symptoms can occur at therapeutic doses, but if they are severe or there is more than one, indication of toxicity

Tremor (frequent), sedation, decreased cognition, incoordination 

Lithium concentrated in thyroid gland and causes decreased thyroid function in most patients, but effects are reversible 

Monitor TSH levels every 6-12 months 

Nephrogenic diabetes insipidus 

Inhibition of adenylate cyclase leads to decreased aquaporin 2 channels in apical membrane of collecting tubule of kidney; resistant to vasopressin 

Rx: amiloride and thiazide diuretics can be used to treat polyuria -- MOA: due to decrease in ECF and increased reabsorption of sodium and water in proximal tubule; may also increase aquaporin 2 levels 

Tubulointerstitial nephropathy (chronic LI treatment), n/v/d/weight gain, dermatitis, exacerbation of psoriasis, hair loss, and acne, reversible increase in PMN leukocytes (can be exploited to treat low WBC states), may be used in pregnancy but has been associated with Ebstein's anomaly 

Possible alternative would be a typical antipsychotic; clearance of lithium increases during pregnancy 

Symptoms: convulsions, coma, confusion, coarse hand tremor, muscle rigidity, fasiculations, ataxia 

Therapeutic overdose is due to lithium accumulation due to reduced sodium levels that may happen through use of diuretics

Values of 2 meq/L can induce potential toxicity 

Hemodialysis is effective if toxicity is severe with significant CNS effects and renal impairment

In more mild toxicity treat with fluids 

Lithium often used in combo with haloperidol -- may produce more EPS (use atypicals instead)

NSAIDs, ACEi, and diuretics may decrease clearance of Lithium