SCHIZOPHRENIA

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SCHIZOPHRENIA
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It's been around awhile....

• Greeks clearly described 1st 2nd centuries A.D.
• Middle Ages- willful evil
• 18th century - its a disease
• 19th - pt.s txd w/ compassion
• 20th - effective pharmacological tx modern
  disease formulations applied to the disease

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• Loss of touch with reality
• Decreased ability to think coherently
  comprehend environment
• Intellectual emotional responses
  inappropriate
• Perceptual disturbances
• Hallucinations (auditory)
• Delusions (false beliefs)

Characteristics
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Schizophrenia

• Most common psychosis
• 1 worlds population (1100)
• Onset late teens early 20s
• Recovery varies, best after 50 yr. One study 50
  patients no psychotic symptoms after 10 yrs

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Schizophrenia - Symptoms2 categories

• POSITIVE Observe behavior/function not normally
  there.
• Hallucinations - sensory perception w/o external
  stimulation tactile, auditory
• Delusions - baseless beliefs
• Persecution
• Grandeur
• Thought disorder, bizarre behavior
• loose associations (word salad)
• silliness, agitation, grooming
• Positive symptoms can Wax and Wane

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Negative Symptoms

• Flattened affect - face immobile unresponsive
• Thought poverty - poverty of speech,
  uncommunicative
• Avolition - inability to initiate or participate
  in goal directed activities (sit motionless,
  incommunicative)

• Stable
• Not related to symptoms
• Different disease process?
• Resistant to tx

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Risk Factors

• Genetics
• Perinatal
• Winter birth
• Each factor confers a small risk, but when they
  occur together, risk multiplies

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Risk Factors

• Genetics - it runs in families.
• Closer the genetic relation, the higher the
  probability

Clear evidence that schizo. Aggregates in
families. Must interact w/ other risk factor
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Association between Perinatal Accidents
Schizophrenia

• Pathological processes during brain development
  (in utero) unfold when brain reaches adult
  anatomical state
• Abnormalities lead to activation of pathological
  circuits during adolescence leading to emergence
  of symptoms
• Increases risk by 1

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Markers?

• Low birth weight
• Prematurity
• Preeclampsia
• Prolonged
• Hypoxia
• Fetal distress

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Brains have cellular irregularities that happen
in development
Hippo neurons very vulnerable to hypoxia
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Winter Birth

• More winter births among schizophrenics
• Very replicable

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Structural Abnormalities

• Enlarged ventricles
• Due to reduction in temporal lobe
• Poorer response to drugs
• High degree cognitive impairment social
  maladjustment
• Earlier age onset
• Negative symptoms

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Functional Abnormalities

• PET - less metabolic activity in frontal lobes
  than normals

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History

• B.C. to 1950s - TXs
• Slaughtered
• Whirled into unconsciousness
• Dunked in icy water
• Injected w/ insulin until coma
• Electroshocked
• Lobotomized
• 1950 -Henri Laborit
• Phenothiazine (Chlorpromazine)
• 1952 - Jean Delay reports antipsychotic effects

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Thorazine Introduced Clinically 1955
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The Dopamine (DA) Hypothesis

• Direct DA receptor antagonists antipsychotic
• Potency correlated w/ ability to bind w/ D2
  receptors
• DA agonists make schizophrenia worse

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Traditional Antipsychotics Produce

• Parkinsonism (DA dysfunjction)
• Tremors
• Akinesia
• Compulsive restlessness
• Tardive Dyskinesia
• Involuntary movements of face jaw (sucking, lip
  smacking, tongue protrusion)
• Can be permanent

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Some Parkinsons Patients Show Signs of
schizophrenia
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Amphetamine Psychosis

• Some addicts able to take up to 3000mg/day (5 mg
  wakefulness, appetite suppress)
• Many develop symptoms of paranoid schizophrenia
• Amphetamines promote release of DA and block
  re-uptake
• Reverse with DA antagonist

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DA Brain Systems
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Mesolimbic

• Hyper DA in limbic areas (especially amygdala)
• Positive symptoms associated w/ temporal lobe
  dysfunction

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Mesocortical

• DA important in regulating frontal lobe function
• Hypo DA in frontal areas negative symptoms
• DA blocking agents not helpful

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Glutamate is Part of the Story!

• Glutamate antagonists (e.g. phencyclidine (PCP))
  induce and - symptoms in non-schizophrenics
• Unmedicated schizophrenics more sensitive than
  normals to effects of glutamate antagonists
• Long-term glutamate hypofunction causes decreased
  mesocortical DA activity excess subcortical
  activity in lab animals

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How Does it all Fit?
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Traditional Antipsychotic Drugs(typical)

• Block DA receptors in many brain areas
• 30-50 - poor response
• 30-60 - Parkinsonism
• Negative symptoms not helped
• Subjectively unpleasant to take
• Some cognitive deficits
• Tardive dyskinesia

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New Antipsychotic Drugs Atypical

• Negative positive symptoms
• Block D2 receptors in limbic, cortex, not too
  many in motor system
• NO Parkinsonian
• Affect 5-HT which modulates cortical DA activity
• agranulocytosis

Clozapine Risperidone molindone, loxapine
pimozide
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In General, antipsychotics are...

• Readily absorbed from GI cross B-B-B
  placenta easily
• Have long half lives
• Rarely lethal
• Rarely abused
• No signs of tolerance or physical dependence
• Reproductive - can be harmful