Pharmacology of Psychoses/Mood Disorders

Question 1

Dopamine theory of schizophrenia related to MOA of antipsychotics

Answer 1

• overactivity of brain dopaminergic pathways, esp. @ mesolimbic pathway __​==> positive sx of schizophrenia
  
  • mesolimbic = integration of sensory input and motor responses + affective/emotional data
• • hypoactivity of (dopamine-activated) cells @ mesocortical pathway ==> negative sx of schizophrenia
    
    • mesocortical = involved in communication adn social abilities
• MOA of antipsychotic drugs: via block of D2 receptors, effective in blocking positive sx
  *

Question 2

Evidence for the dopamine hypothesis

Answer 2

• Virtually all antipsychotics block CNS dopamine receptors (postsynaptic D2).
• Drugs that increase dopaminergic activity (levodopa-dopamine precursor; cocaine- reuptake blocker, amphetamine-dopamine releaser) can aggravate or produce schizophrenia.
• Positron emission tomography (PET) scans show decreased D2 dopamine receptor densities in prefrontal lobes of schizophrenics, but increased densities in caudate nucleus (striatum).

Question 3

Evidence counter to the dopamine hypothesis

Answer 3

• Block of D2 receptors occurs immediately while antipsychotic effects take 3-6 weeks, suggesting secondary effects may be more important than direct effect of receptor block.
• Clozapine is weak D2 blocker but still is an effective antipsychotic agent.
• Additional evidence for the role of gluatamate and seratonin systems in psychosis as well.

Question 4

Chlorpromazine: drug category, uses, NT/receptor

Answer 4

• typical antipsychotic
• treats + sx
• MOA
  
  • primary: D2 receptor antagonist
  • secondary: some antagonist actions at muscarinic, alpha-1 adrenergic, and histamine receptors

Question 5

Chlorpromazine: incidence of SE, factors in choosing drug

Answer 5

• SE
  
  • medium extrapyramidal toxicity
  • high sedation (via antimuscarinic/antihistamine)
  • high ANS effects
    
    • dry mouth (antimuscarinic)
    • orthostatic hypotension (alpha1 block)
• Factors in choice
  
  • Low clinical potency, high dose needed to achieve anti-psychotic effects

Question 6

Haloperidol: drug class, use, NT/receptor

Answer 6

• typical antipsychotic
• treats positive sx
• MOA:
  
  • very good D2 antagonist
  • minor alpha1 antagonist

Question 7

Haloperidol: SE, tx of SE, factors in drug choice

Answer 7

• SE
  
  • low sedation
  • high extrapyramidal sx (due to dopaminergic blockade):
    
    • acute dystonia
      
      • tx: antimuscarinic
    • akathisia
      
      • tx: reduce dose/change drug
    • pseudoparkinsonism
      
      • tx: anticholinergic
    • tardive dyskinesia
      
      • tx: prevention
  • some orthostatic hypotension (via alpha1 block)
• Factors in drug choice
  
  • high efficacy, low dose
  • SE profile

Question 8

Clozapine: drug class, use, NT/Receptor

Answer 8

• atypical antipsychotic
• treats negative sx & tx-resistant individuals
• MOA
  
  • high 5HT2/D2 block (low D2/5HT2)
  • muscarinic antagonist
  • alpha1 antagonist

Question 9

Clozapine: SE, factors in drug choice

Answer 9

• SE
  
  • low sedation
  • Autonomic
    
    • orthostatic hypotension (alpha1 block)
  • agranulocytosis = low WBC production
  • weight gain
• factors in drug choice
  
  • medium potency
  • reserved for pt.s that are refractory to other drugs

Question 10

Risperidone: drug class, use, NT/Receptor

Answer 10

• atypical antipsychotic
• treats negative sx & tx-resistant individuals
• MOA
  
  • low D2/5HT2 = good 5HT2 block

Question 11

Risperidone: SE, factors in drug choice

Answer 11

• minimal SE @ low doses
• Factors in drug choice
  
  • high potency + low SE

Question 12

Olanzapine: drug class, use, NT/Receptor

Answer 12

• atypical antipsychotic
• treats negative sx & tx-resistant individuals
• MOA
  
  • low D2/5HT2 = good 5HT2 antagonist

Question 13

Olanzapine: SE, factors in drug choice

Answer 13

• SE
  
  • medium sedative effects
  • weight gain
• factors in drug choice
  
  • high potency

Question 14

Aripiprazole: SE, factors in drug choice

Answer 14

• minimal SE
• high potency

Question 15

Aripiprazole: drug class, use, NT/Receptor

Answer 15

• atypical antipsychotic
• treats negative sx & tx-resistant individuals
• MOA
  
  • low D2/5HT2 = good 5HT2 block

Question 16

Characteristics of typical antipsychotics

Answer 16

• high D2 / 5HT2A ratio = good D2 block ==>good efficacy against positive symptoms of schizophrenia.
  
  • D2 block ==> extrapyramidal toxicity.
• high clinical potency (haloperidol-effective in lower doses)
  
  • greater D2 blocking activity
  • greater risk of extrapyramidal toxicity
• low clinical potency (chlorpromazine-effective in higher doses)
  
  • do not block D2 receptors as well
  • less extrapyramidal toxicity
  • larger doses necessary ==> side effects at other receptors (antimuscarinic [dry mouth, sedation], α1-blockade [hypotension], antihistamine [sedation]).

Question 17

Characteristics of atypical antipsychotics

Answer 17

• Characterized by a low D2 / 5HT2A ratio corresponding to poor D2 block yet good efficacy in schizophrenia (an “atypical” observation).
• The good 5HT2A block is thought to be associated with good efficacy against negative symptoms of schizophrenia as well as efficacy in treatment-resistant individuals.

Question 18

Summary of pathophys of schizophrenia + pharmacotherapy on brain pathways

Answer 18