Schizophrenia and Antipsychotic Treatment Stacy Weinberg



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Schizophrenia and Antipsychotic Treatment

  • Stacy Weinberg

  • 3 April 2007


What is it?



Types

  • Catatonic Type

    • Either in position or speech (imitating others)
    • Very rare
  • Disorganized Type

    • Disturbance in behavior, speech, and thought
    • Flat affect, eccentric
  • Paranoid Type

    • Delusions and auditory hallucinations
    • Cognitive functioning remains intact
  • Residual Type

    • Have been previously diagnosed but no longer show prominent symptoms; still have other symptoms
  • Undifferentiated Type



Positive Symptoms

  • Disturbances of thought processes

  • Delusions

  • Hallucinations

  • Erratic/extreme emotions

  • Very slow or fast movement, catatonia

  • Behavioral changes



Negative Symptoms

  • Lack of interest/enjoyment in activities

  • Low energy/motivation

  • Blank facial expression, less facial variability

  • Inability to make or keep friends

  • Difficulty initiating activities

  • Social isolation



Causes - Dopamine Hypothesis

  • Genetic aspect

  • Most think it involves dopamine:

    • Elevation of D2 monomers, decrease of dimers
    • Increased release of dopamine
      • 2x higher
      • When given amphetamine, 2x more
      • dopamine is released than control


Other Hypotheses

  • Dopamine hypothesis not agreed on by everyone

  • Some think excitatory amino acids like glutamate could play a role

    • One type of glutamate receptor, NMDA: NMDA antagonists (ex ketamine) can induce psychotic symptoms in non-schizophrenic patients
    • Found increase of NMDA receptors in postmortem studies of schizophrenic brains


Types of Drug Treatment

  • Typical Antipsychotics

    • Dopamine antagonists
  • Atypical Antipsychotics

  • Combination Drugs



Typical

  • Tend to produce Extrapyramidal side effects:

    • Parkinsonism – tremors, rigidity, slowness of movement, temporary paralysis
    • Dystonia – involuntary muscle contractions
    • Akathisia – inability to resist urge to move
    • Tardive dyskinesia – involuntary movements of the mouth, lips, and tongue
      • Chewing, puckering, grimacing, etc.


Typical - Phenothiazines

  • Dopamine D2 receptor antagonists

  • Chlorpromazine first developed from promethazine, first tricyclic antihistamine



Haloperidol

  • Butyrophenone

  • Used in 1970s almost exclusively

  • No anticholinergic effects – therefore used in patients with delirium



Atypicals

  • Atypicals do not induce EPSE

  • Block D2 receptors and 5-HT seratonin receptors (decreases EPSE)

  • As opposed to typicals, these are more loosely bound to D2 receptors

    • Easier dissociation
    • Shown that higher occupation of D2 receptors by drug, higher incidence of EPSE


5-HT seratonin receptors

  • Blocking 5-HT seratonin receptors decreases negative symptoms and EPSE

    • Mechanism is unknown
    • Seratonin inhibits dopamine release
    • Positive symptoms associated with hyperdopaminergic condition in limbic lobe – more D2 receptors here, so D2 blocking prevails
    • Negative symptoms associated with hypodopaminergic condition in frontal lobe – more 5-HT receptors here, so seratonin inhibits dopamine release – stabilizes dopamine level




Clozapine

  • First atypical (1990)

  • Most dangerous atypical: risk of agranulocytosis (severe decrease in WBC count)

  • Most effective in reducing EPSE, also in reducing negative symptoms

    • Increases Fos-positive neurons in the prefrontal cortex (shown to affect negative symptoms)


Risperidone

  • Low doses needed

  • Predominantly blocks D2, then 5-HT

    • Does not exhibit multireceptor action
  • Lacks anticholinergic activity – makes it better for youth, elderly

  • Problem – increases prolactin levels (shouldn’t give to people with breast cancer)



Olanzapine

  • Zyprexa is number one antipsychotic in sales (Eli Lilly)

  • Exhibits multireceptor action

  • Good for controlling mood symptoms

  • Available in a wafer

  • Problems: Sedation and

  • weight gain



Combinations

  • Example is Symbyax

    • Combination of olanzapine and fluoxetine (Prozac)
    • Can also treat bipolar disorder
  • Combination of ziprasidone and clozapine

    • Can be used to combat treatment resistance
  • Combination of aripriprazole and clozapine




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