Psychosis -- Lichtblau

Question 1

What is psycosis chemically?

Hint: This is a theory…

Answer 1

The dopamine hypothesis states that psycosis is caused by a general increase in DA activity (esp the D₂ subtype) in the CNS, especially the mesolimbic pathway (know this?)

Question 2

First Generation Antipsychotics (FGAs)

MOA and Examples…

Answer 2

• D2 receptor antagonist in limbic system (striatum!!) → disinhibition?
• Most effective against positive (hallucinations etc) symptoms
• DA (generally) blocked generally in rest of brain
  
  • Leads to EPS and other adverse effects

Examples: Chlorpromazine (Thorazine), Haloperidol (Haldol)

Question 3

Mesolimbic Pathway

Answer 3

• tegmentum (midbrain) → nucleus accumbens (limbic system)
• Proposed area of brain that mediates the positive symptoms of schizophrenia
• Block D2 DA receptors → ↓+ symptoms (antipsychotic drugs)
• Site of + symptoms mimicked by chronic (ab)use of drugs that↑DA
  
  • Amphetamine and cocaine

Question 4

Mesocortical Pathway

Answer 4

• tegmentum (midbrain) → frontal and limbic cortex
• mediates the negative (and cognitive?) symptoms of schizophrenia
• Decreasing DA levels or activity may produce or worsen negative symptoms
• Helps explain why negative symptoms are unaffected or worsened by antipsychotics that ONLY block DA receptors
  
  • Second generation antipsychotics (SGAs) affect both DA and 5-HT receptors and are more beneficial in treating negative symptoms

Question 5

Nigrostriatal Pathway

Answer 5

• substantia nigra (midbrain) → basal nuclei
• regulates posture and voluntary movement
• FGAs block the DA receptors in striatum, resulting in a Parkinsonism-like syndrome (extrapyramidal symptoms, EPS)
• **SGAs – less likely to produce these symptoms **

Question 6

Tuberoinfundibular Pathway

Answer 6

• hypothalamus → anterior pituitary
• DA inhibits prolactin (hormone that prepares the breasts for lactation in women) release
• With FGAs female patients may experience
  
  • Galactorrhea
  • Amenorrhea
  • Sexual dysfunction

Question 7

Second Generation Antipsychotics

MOA

Answer 7

• block D2 receptors AND 5-HT receptors
• Presynaptic 5-HT₂ receptors regulates DA release
  
  • Activating 5-HT₂ receptors blocks release of DA
  • **Blocking 5-HT₂ receptors increases release of DA **(for striatum –> decreased EPS!; less neg symp, less prolactinemia, less postive symp)

Ex = Clozapine, Risperidone (Risperdal), Olanzapine (Zyprexa), Quetiapine (Seroquel), Aripiprazole (Abilify)

Question 8

Tardive Dyskinesia (TD)

What is it?

Answer 8

slow involuntary repetitive body motions

more prevelent with FGAs

incidence is zero with clozapine

may not be reversible, which is in contrast to the the EPS (parkinsonian symp).

Question 9

What is so special about clozapine?

Answer 9

SGA

no tardive dyskinesia

has risk of agranulocytosis