1 in 100 people have had a schizophrenia episode... more than 2.2 million Americans.

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• 1 in 100 people have had a schizophrenia
  episode... more than 2.2 million Americans.
• Previously- talked about 1/3 rule
• 1/3 take meds and get better 1/3 take med but
  have ups and downs 1/3 medication does little to
  help
• NEW MEDS PROBABLY HAVE CHANGED THESE NUMBERS!!

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Slight diversion how to study whether genetics
plays a role in a disorder?

• twin studies
• look at monozygotic (1 egg) twins 99 genes in
  common vs dyzgotic twins 50 genes in common

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Other ways to look at role of genetics

• Adoption studies
• allows you to look at role of environment vs genes

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Adoption Studies 2 potential scenarios
biological parent (shares 50 genes) adoptive parent (shares env) child
has schizophrenia normal home increased incidence of schizophrenia

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Adoption Studies 2 potential scenarios
biological parent (shares 50 genes) adoptive parent (shares env) child

normal home has schizophrenia increased incidence of schizophrenia
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Symptoms of schizophrenia

• positive and negative symptoms
• positive symptoms
• things that you can see hallucinations,
  delusions, etc
• negative symptoms things that are absent
• social withdrawal

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The Way We Used to Think About Schizophrenia

• positive symptoms could be treated medically
• negative symptoms would not respond to drugs
  but rather was brain damage as a consequence of
  whatever schizophrenia did to the brain

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Recent History in Pharmacotherapy of Schizophrenia

• First drugs to treat schizophrenia appeared in
  early 1950s major impact!
• called traditional neuroleptics, antipsychotics
• treat the positive symptoms
• Now atypical neuroleptics 1989 1999
• treat positive and negative symptoms

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Recent txt history

• 1950s chlorpromazine (Thorazine) and
  haloperidol (Haldol)
• still the most widely used and cheapest way to
  treat positive symptoms
• Other Uses for chlorpromazine
• nausea and vomiting, chronic hiccups, severe
  itching, manage psychotic component in acute
  mania, to treat alcohol hallucinosis

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What is the main mechanism of action?

• Blocking DA receptors
• Resulted in the DA theory for schizophrenia
• D2 receptor subtype important
• how well the drug binds to D2 receptor is clearly
  linked to reduction in positive symptoms

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Evidence for the DA Theory for Schizophrenia

• drugs that block DA
• drugs that increase DA activity
• l-dopa
• used to treat Parkinsons Disease
• potential side effect
• amphetamine and cocaine
• acute psychosis

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So where are the DA pathways in the brain?

• mesolimbic DA pathway
• important for reward and probably some of the
  positive symptoms associated with schizophrenia
• nigrostriatal DA pathway
• important for movement (pathway for Parkinsons
  Disease)

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So what are some of the side effects with
antipsychotic drugs?

• a lot of problems related to movement

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• Parkinson like symptoms brought on by medication
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• characteristics rigidity, tremor, difficulty
  initiating movement, flat affect
• dystonia spastic contractions of discrete
  muscle groups 10
• occurs most commonly in neck, eyes and torso
  causes great distress

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• akathisia-
• complain of an inner sensation of restlessness
  and an irresistible urge to move various parts of
  body (often seen as pacing and inability to sit
  still)
• 20 25 of patients show it
• frequent cause of noncompliance

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tardive dyskinesia

• probably most serious of the movement disorders
  
• involuntary movement disorder caused by sustained
  exposure to antipsychotic medication
• most commonly affects oral facial region so
  tongue protrusions, lip smacking, neck jerking,
  etc
• until recently considered a permanent effect

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Is it only DA that is affected by these drugs?

• NO! these drugs have effects on multiple other
  neurotransmitters that also have significant side
  effects

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• 1 in 3 patients who start an antipsychotic will
  either switch medications or discontinue their
  medication within a year.
• Why do they discontinue? At least 1/3 appear to
  discontinue because of the side effects of the
  medication.

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Common side effects

• Sedation- most common single side effect of
  antipsychotic medication
• often most pronounced early in treatment
• variety of adverse effects, can occur in 10 50
  of treated patients
• some patients experience problems with
  thermoregulation
• weight gain up to 40 treated patients gain
  significant weight

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atypical neuroleptics

• first atypical neuroleptic was clozapine
• people who had not been able to leave hospital
  for 25 years were suddenly better!

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atypical neuroleptics

• first atypical neuroleptic was clozapine
• effective in proportion of patients that were
  unresponsive to previous medication

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atypical neuroleptics

• first atypical neuroleptic was clozapine
• effective in proportion of patients that were
  unresponsive to previous medication
• reduced negative symptoms

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atypical neuroleptics

• first atypical neuroleptic was clozapine
• effective in proportion of patients that were
  unresponsive to previous medication
• reduced negative symptoms
• reduced tardive dyskinesias

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atypical neuroleptics

• first atypical neuroleptic was clozapine
• effective in proportion of patients that were
  unresponsive to previous medication
• reduced negative symptoms
• reduced tardive dyskinesias
• risky side effects agranulocytosis (potentially
  lethal drop in white blood cells 1 of people
  on drug)

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consequence

• Initially, clozapine cost 36,000/year.
• required contract with nurses that would take
  weekly blood tests
• subsequent costs 12,000/year
• now off patent

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Since clozapine

• 5 new atypicals on the market the most recent
  in 2002 one still in clinical trials
• none are as effective as clozapine for treating
  tardive dyskinesias
• all expensive

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What is different about these atypicals?

• good question some say the drugs bind to D2
  receptors but also to a certain type of 5HT
  receptors
• some say these drugs do not bind quite as well to
  D2 receptors as the more traditional ones

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atypical neuroleptics

• clozapine Clozaril 1989 generic 1998
• risperidone Risperdal - 1994
• olanzapine Zyprexa - 1996
• quetiapine Seroquel - 1999
• ziprasidone Geodon -
• aripiprazole (Abilify)- approved 11/2002
• 13.00/pill?
• iloperidone (Zomaril)
• Novartis phase III program including those with
  schizoaffective and comorbid polysubstance use
• action on all monoaminergic receptor systems

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