Mood Stabilisers

Question 1

Lithium - Mechanism of Action

Answer 1

• Glutamate:
  
  • Acute administration of Lithium increases levels of glutamate via activation of the NMDA receptor and inhibition of its uptake by inhibiting glutamate transporter - antidepressant
  • Chronic administration leads to NMDA receptor downregulation with glutamate reuptake upregulation resulting in lowered levels of glutamate –> mood stabilisation effect.
• Dopamine: Lithium reduces the levels of dopamine at the postsynaptic neuron via second messenger pathway
• GABA: lithium reduces neuronal excitation by increasing the levels of GABA.
• Glycogen Synthase Kinase-3 (GSK-3): GSK-3 plays an important role in modulating synaptic plasticity and maintaining cell structure. Lithium inhibits GSK-3 thus reducing cell death resulting from excitatory neurotransmission.
• Inositol: Inositol is responsible for the maintenance of myo-inositol levels which inturn maintains cell membrane phospholipid concentrations. Lithium reduces excess inositol which inturn stabilises membranes. (Inositol depletion hypothesis).

Question 2

Lithium Pharmacokinetics

Answer 2

• Lithium is orally well absorbed but not metabolized in the liver; it is renally excreted.
• Not protein bound.
• Plasma half life 18 hours initially increasing to 36 hours in chronic use.

Question 3

Lithium Side Effects

Answer 3

1 . ​Renal

• Polyuria common seen in 1/3 of patients. Due to functional antagonism of ADH by lithium ion.
  
  • Can be mitigated by once daily dosing and using K+ sparing diuretics.
• Renal damage - acute due to lithium toxicity or crhonic interstitial fibrosis over years.

2. Endocrine Side Effects:

• Lithium inhibits iodine reuptake, iodotyrosine coupling and thyroxine secretion in the thyroid gland which can result in clincially significant hypothyroidism. (8-19% of patients - more common in woman and during first 2 years of treatment)
• Lithium decreases parathyroid hormone (PTH) calcitonin binding which reduces urinary calcium clearance. This results in hypercalcaemia due to increased PTH.

3. Cardiac side effects:
   * QTc interval prolongation, PR interval prolongation, diffuse T wave inversion and sinus bradycardia - avoid in sick sinus syndrome
4. Neurological side effects

• Tremor and changes in cognition.
• Fine tremor is common. Coarse tremor indicates Lithium toxicity.

5. Haematological
   * Lithium can cause leucocytosis
6. Pregnancy
   * Tertaogenic - commonly Ebstein’s anamology of the tricuspid valve.
7. Skin

• Excacerbation of acne and psoriasis
• Alopecia

Question 4

Carbamazepine - Mechanism of Action

Answer 4

• Prolongs sodium channel inactivation. As a consequence, calcium channel inactivation is prolonged.
• It also reduces glutamate neurotransmission, adenosine A1 receptor antagonism and increase in brain catecholamine activity.
• It inhibits peripheral benzodiazepine receptors and reduces limbic kindling. It interferes with glial cell steroidogenesis.

Question 5

Carbamazepine - Pharmacokinetics

Answer 5

• Hepatic metabolism
• Erratic absorption and bioavailability of about 80%
• 70% plasma protein bound.
• Before autoinduction of CYPA3/4 half-life 24hr, after 2-4 weeks falls to 8 hours.
• Interactions:
  
  • Verapamil and diltiazem can increase levels –> toxicity
  • Valproate inhibits expoxide hydrolase increasing plasma carbamazepine-epoxide levels without changing total plasma levels. Also displaces carbamazepine from plasma proteins –> toxicity
  • Carbamazepine reduces warfarin efficacy
  • Erythromycin can produce carbamazepine toxicity.

Question 6

Carbamazepine - Adverse Effects

Answer 6

• Haematological reactions including agranulocytosis or aplastic anaemia
  
  • Thrombocytopaenia dose related side-effect
• Liver failure and pancreatitis
• SIADH
• Idiosyncratic Stevens-Johnson Syndrome
• Weight gain (40%)

Question 7

Sodium Valproate - Mechanism of Action

Answer 7

• Increases GABA activity via a variety of mechanisms.
• Inhibition of phosphokinase C.
• Functional dopamine antagonism.

Question 8

Carbamazepine Interactions

Answer 8

• Verapamil and diltiazem can increase levels –> toxicity
• Valproate inhibits expoxide hydrolase increasing plasma carbamazepine-epoxide levels without changing total plasma levels. Also displaces carbamazepine from plasma proteins –> toxicity
• Carbamazepine reduces warfarin efficacy
• Erythromycin can produce carbamazepine toxicity.

Question 9

Sodium Valproate - Pharmacokinetics

Answer 9

• Well absorbed with a bioavailability close to 100%
• Quite hydrophilic with a low volume of distribution
• Half life of 9-16 hours
• Highly (90%) protein bound - saturatable
  
  • At high doses increased free fraction may remain in the plasma compartment and thus be cleared by the liver - sublinear kinetics - requires greater increases at higher doses

Question 10

Sodium Valproate - Side Effects

Answer 10

• PCOS - 10% of women on Valproate have new onset PCOD
• Oligomenorrhea in almost all women
• Thrombocytopaenia
• Inhibits haptic enzymes - 5 to 40% of patients experience a persistent but clinically insignificant rise in liver transaminases (transaminitis)
  
  • Risk of liver failure
• Pancreatitis - hypersensitivity reaction
• Teratogenicity - neural tube defects in 1 to 4% of mothers.
• Hyperammonaemia
• Rash and rarely acute dermatitis
• Weight gain (70%)

Question 11

Lamotrigine - Mechanism of Action

Answer 11

• Blockage of voltage-sensitive sodium channels leading tro modulation of glutamate and aspartate release
  
  • Some effect on calcium channels
• Some inhibition of serotonin reuptake and weak inhibition of 5-HT3 receptors

Question 12

Lamotrigine - Pharmacokinetics

Answer 12

• Lamotrigine achieves peak concentrations within about 3 hours
• Oral bioavailability of about 98%
• It is 56% plasma protein bound
• T1/2 of 24 to 36 hours
• Enzyme inducers (phenytoin, phenobarbital or carbamazepine) reduce half life
• Valproate increases half life

Question 13

Lamotrigine - Side Effects

Answer 13

• Significant risk of Steven Johnson Syndrome (SJS) - expecially when administered with Valproate
  
  • Starts with rash, pharyngitis and fever -> systemic involvement follows quickly.
• Dizziness, ataxia, headache, sedation, tremor and nausea.

Question 14

Topiramate - Mechanism of Action and Side Effects

Answer 14

• Selective inhibitor of Glutamate AMPA receptors, blocks Na receptors and potenitates GABAa receptors
• Can produce word finding difficulties (anomia) and poor concentration
• Weight neutral and can cause weight loss.