Lithium and Mood Stabilizers

Question 1

Lithium

Indications

Answer 1

• Acute Mania
  
  • Takes days to weeks to achieve effect so used along with other agents
• Prevention of recurrent bipolar affective illness especially manic episodes
  
  • Not considered as good for rapid cycling or mixed episodes
• Severe recurrent depression with cyclic pattern
• Sometimes combined with antipsychotic drugs to treat psychosis
• Unipolar depression that do not respond to antidepressants, who may actually be bipolar

Therapeutic concentrations of lithium ⇒ almost no discernible psychotropic effect in normal control humans

Differentiates lithium from all other psychoactive drugs

Question 2

Lithium

Absorption & Distribution

Answer 2

• Absorption
  
  • Almost completely absorbed from GI tract
  • Available in extended-release tablet to prolong action
• Distribution
  
  • Distributed in ECF with gradual accumulation in various tissues to different degrees
  • Final volume of distribution approaches total body water
  • Lithium slowly passes through the BBB ⇒ at steady-state, CSF concentrations ≈ 40% of plasma

Question 3

Lithium

Metabolism & Excretion

Answer 3

• ~ 95% of a single dose is eliminated in the urine
  
  • T_½ = 20-24 hrs
• Repeated doses ⇒ shortens T_½
  
  • After one-year, T_½ = 2.4 days
• Shorter T_½ in geriatric pts and pts w/ impaired renal function
• Considerable pharmacokinetic variations b/t pts but relatively stable w/in pts
• Low therapeutic index ⇒ high risk of toxicity
  
  • Requires regular monitoring of blood drug concentrations
• Anything that ↑ renal salt absorption from proximal tubule ⇒ ↑ lithium absorption
  
  • Avoid dehydration ⇒ ↑ lithium in the serum
  • Excess Na⁺ ⇒ ↑ elimination of lithium
  • ↓ Na⁺ ⇒ ↓ elimination of lithium
• Optimal serum concentration: 0.6-1.3 mEq/L [measured 10 hours after PO dose]
  
  • Lower doses may be used when combined with other agents
  • Titration to higher doses under very close supervision, generally in-patient

Question 4

Lithium

Mechanism of Action

Answer 4

Exact mechanism unknown

Several proposed mechanisms:

• ⊗ Inositol monophosphatase
  
  • ↓ brain inositol ⇒ ⊗ receptor-activated PIP₃ hydrolysis ⇒ ⊗ formation of inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG)
  • Depletion of phosphoinositide precursors ∝ activity of the cell (or PLC)
  • Mania may be associated with a state of neuronal hyperactivity ⇒ lithium may selectively inhibit these pathways
• ⊗ G-protein coupled receptors
  
  • ⊗ NE stimulated adenylyl cyclase
  • ⊗ some G-protein coupled receptors
  • Leads to one major and one minor side effect
    
    • ⊗ vasopressin (ADH) leads to polyuria
    • ⊗ TSH leads to subclinical hypothyroidism
• ⊗ Growth factor pathways
  
  • GF acts via glycogen synthase kinase (GSK-3) ⇒ ⊕ cell death
  • Lithium ⊗ GSK-3 ⇒ neuroprotective effects and long-term plasticity

Question 5

Lithium

Toxic Reactions & Side Effects

Answer 5

• CNS
  Sx can occur @ therapeutic doses but if more severe or > 1 occurs ⇒ indication of toxicity
  
  • Tremor - frequent, occurs at peak blood levels after therapeutic doses
  • Sedation
  • ↓ cognition
  • Incoordination
• Thyroid
  
  • Lithium is concentrated in the thyroid gland
  • Causes ↓ thyroid function in most pts
  • Effects are reversible
  • Monitor TSH levels every 6-12 months
• Polydipsia & polyuria
  
  • Nephrogenic diabetes insipidus (common)
    
    • ⊗ adenylate cyclase ⇒ ↓ aquaporin 2 channels @ apical membrane of the collecting tubules
• Other side effects
  
  • Tubulointerstial nephropathy w/ chronic Li⁺ treatment
    
    • Monitor plasma creatinine and urine volume
  • Nausea, vomiting, diarrhea, weight gain
    
    • Edema may cause weight gain but does not account for weight ∆ observed in up to 30% pts taking lithium
  • Dermatitis, exacerbation of psoriasis, hair loss, and acne
  • Reversible ↑ in polymorphonuclear leukocytes w/ chronic Li⁺ treatment
    
    • Can be exploited to treat low leukocyte states

Question 6

Nephrogenic Diabetes Insipidus

Treatment

Answer 6

Nephrogenic diabetes insipidus (common)

⊗ adenylate cyclase ⇒ ↓ aquaporin 2 channels @ apical membrane of the collecting tubules

• Resistant to vasopressin
• Paradoxically amiloride and/or thiazide diuretics can be used to tx polyuria
  
  • MOA is unclear but may be due to ↓ ECF volume & ↑ reabsorption of Na⁺ and water in the proximal tubule
  • Some evidence that thiazide diuretic may ↑ aquaporin 2 levels
• Thiazide diuretics ↓ lithium clearance ⇒ need to adjust lithium dose down

Question 7

Lithium Use During Pregnancy

Answer 7

• May be used in pregnancy
• ? association between lithium use during 1^st trimester and cardiovascular malformations such as Ebstein’s anomaly in neonates
  
  • Congenital defect in the tricuspid valve
• Absolute risk is still low
  
  • Some clinicians consider it to be relatively safe during pregnancy
• Possible alternative would be a typical antipsychotic
• Clearance of lithium ↑ during pregnancy

Question 8

Li⁺ Overdose

Answer 8

• Possible symptoms are: convulsions, coma, confusion, coarse hand tremor, muscle rigidity, fasciculations, and ataxia
• Therapeutic overdose due to lithium accumulation
  
  • Diuretics ⇒ ↓ serum Na⁺ ⇒ ↓ lithium clearance
  • Changes in renal function or pregnancy
• Values of 2 meq/L in serum indicate potential toxicity
• Treatment:
  
  • Hemodialysis is effective if toxicity is severe with significant CNS side effects and renal impairment
  • In more mild toxicity, treat with fluids

Question 9

Lithium

Drug Interactions

Answer 9

• Lithium is often used in combo with haloperidol ⇒ may produce more extrapyramidal symptoms
  
  • Use atypicals instead
• Diuretics, NSAIDS, ACE inhibitors ⇒ ↓ clearance of Lithium

Question 10

Valproate

Indications as a Mood Stabilizer

Answer 10

• Acute manic phase
• Maintenance, prevention of recurrence of mania
• May be good for rapid cycling or mixed episodes
• In practice, combo of agents may be required (ex. Lithium + valproate)

Question 11

Carbamazepine

Indications as a Mood Stabilizer

Answer 11

• 2^nd line agent when pt cannot tolerate or does not respond to lithium
• Acute mania
• Maintenance, prevention of recurrence of mania

Question 12

Lamotrigine

Indications as a Mood Stabilizer

Answer 12

• Maintenance, prevention of recurrence of both mania and depression
• Unique effect on depressed phase & preventing recurrence of depression
• Anti-depressants can unmask mania ⇒ mood instability
  
  • Some clinicians use lamotrigine as replacement for antidepressants

Question 13

Atypical Antipsychotics

Indications as a Mood Stabilizer

Answer 13

Use in bipolar disorder:

• May be used alone for acute mania
  
  • Atypicals preferred over typicals
• May be used w/ Lithium for acute mania
  
  • To achieve therapeutic goal more rapidly
• Olanzapine and aripiprazole approved for maintenance
• Atypicals may be used w/ other agents for maintenance