Transcript No Slide Title

Mind and brain are two sides of one coin;
Disorders of the mind* are disorders of the brain.
* schizophrenia, depression, anxiety, psychopathy, etc.
Schizophrenia
• Clinical features
• Etiology (cause)
– Genetic
– Environmental
• Neurobiology & Pharmacotherapy
Clinical features
• Positive symptoms
– Hallucinations
– Delusion
– Disorganized Speech
High Dopamine
– Socially awkward behavior (disorganized)
• Negative symptoms*
– Poverty of speech
– flat affect, apathy, anhedonia
– Decreased motor activity
• Cognitive symptoms*
– Working memory, attention
* non-specific
A very debilitating disease
Hypofrontality
male
All ethnic groups/geography
Lifetime prevalence = 1%
First diagnosis at 20 yrs of age
Prodrome at 17 yrs of age
female
10
20
30
40
50
years
Jennen-Steinmetz et al 1997
Early detection is key, as delayed
treatment:
- increases brain damage,
- shows less recovery
Some signs present at childhood:
- neuromotor functions
- sociability
- emotions
prodrome 1st acute
episode
relapse
relapse residual
phase
Time course:
- positive symptoms are evident in the acute episodes
- negative symptoms increase gradually (although they can
precede the positive ones, as in the prodrome)
Schizophrenia
• Clinical features
• Etiology (cause)
– Genetic:
– Environmental
• Neurobiology & Pharmacotherapy
Given that somebody is schizophrenic, what is the likelihood that
you will suffer from schizophrenia? (in %)
identical twin
48
fraternal twin
17
1
9
sibling
1
0
20
40
60
general
population
Increased risk with closer genetic distance
If biological parent is schizophrenic: 17%
(thus schizophrenia is not due to a single gene mechanism)
Environmental changes start in utero
Identical genes
Identical genes
‘Same’ environment
Slightly different environment
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Higher concordance for schizophrenia Lower concordance for sch
Only 17% chance of passing schizophrenia to your offspring;
- Thus, it’s not due to a single gene (unlike Huntington’s)
- May be genes impart susceptibility, and other factors trigger it.
How likely it is that your offspring will be schizophrenic?
If you are schizophrenic:
17%
If your fraternal twin is schizophrenic:
2%
If your identical twin is schizophrenic:
17%
The identical twin is genetically predisposed to suffer the
disease (& thus passes the genetic risk to his offspring).
The identical twin is susceptible to the disease but its
triggering environmental factor was absent (susceptibility
hypothesis).
Same story, as told by your textbook
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- Age of father (not of mother)
- Spermatocytes divide more frequently than oocytes, so
increase chance of mutation (it’s not a Y chromosome mutation)
- Environmental impact on a genetic factor
Schizophrenia
• Clinical features
• Etiology (cause)
– Genetic:
– Environmental
• Neurobiology & Pharmacotherapy
Environmental stress: maternal flu during pregnancy, malnourishment, obstetrics
Viral hypothesis (flu)
• Seasonal (previous slide)
• Urban
• Flu epidemic
Maternal influenza during
fetal development (2nd
trimester)
Stress hypothesis
• Flu is just a stressor
• Other stressors during 2nd trimester also increase risk:
– Underweight mother
– Underweight newborn
– Famine (due to thiamine deficiency post-famine?)
– Your husband is killed
– Increased cortisol
• stress video
• may also explain disease onset in adolescence
Of those showing warning signs (prodromal phase)
• 1/3 gets better as they enter adulthood
• 1/3 continues to experience mild symptoms
• 1/3 develops schizophrenia or other psychosis
This latter group has the higher cortisol levels at prodrome
Cortisol levels increase with puberty (even in normal kids)
a disruptive family environment (stressor) is a risk factor.
Further evidence for cortisol hypothesis: in animal models, cortisol
increase during pregnancy leads to abnormal hippocampus in
the offspring
Obstetric complications
• Stress and reduction in brain oxygen during:
– pregnancy
– labor & delivery
• Evidence from animal models:
– Fetal hypoxia leads to neuropathology similar to
one observed in schizophrenia:
• Enlarged ventricles (reduced brain weight)
• No gliosis
• Most predictive for those without genetic influence
Abnormal brain development
Pre-natal:
•
•
Neuromotor oddities (e.g, posture)
Minor physical abnormalities (e.g., asymmetrical ears)
Post-natal:
•
Neuromotor oddities (e.g, posture)
•
Traumatic brain injury
•
•
•
•
•
synaptic pruning
loss of dendrites,
no gliosis (i.e., scar tissue)
hypofrontality
small Hippocampus
Schizophrenia
• Clinical features
• Etiology (cause)
– Genetic:
– Environmental
• Neurobiology & Pharmacotherapy
Neuroanatomy:
- Enlarged ventricles
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-Childhood onset (13 yold)
-frontal relatively spared!
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First episode, never medicated patients
AX Task
AY requires inhibition
BX requires working memory (retain context)
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• PCP (phenyciclidine) causes
– Positive symptoms
– Negative & cognitive symptoms
• Thus, it is a good drug for testing how schizophrenia develops
• PCP:
–
–
–
–
Inhibits NMDA receptors (glutamate) in frontal lobe
decreases frontal lobe activity, which in turn
causes hiperactivity in mesolimbic dopaminergic cells and
therefore triggers positive symptoms
• PCP:
– Activates dopaminergic cells that project to n. accumbens (positive s)
– Also inhibits dopaminergic cells that project to frontal lobe (negative s)
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Copyright © Allyn & Bacon 2007
• When used chronically,
PCP impairs frontal tasks
(e.g., object retrieval with
detour)
• Antipsychotic drugs:
– improve performance
– increase dopamine
release in prefrontal
cortex
• In sum, low DA and/or
glutamate in frontal cortex
can lead to high DA in
VTA
Evidence for the role of dopamine in positive symptoms
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•
•
•
Antipsychotic drugs (D2 blockers)
DA agonists (e.g., cocaine)
Increased DA or increased DA receptors?
PET study using amphetamines (ethics?)
Hypofrontality comes first: what causes it?
• Synaptic pruning:
– Reduced dopaminergic and/or glutamatergic activity in
frontal lobe
• Gaba:
– These neurons modulate glutamatergic activity
– They have to migrate longer distances in development
(so more opportunities for environmental insults)
Pharmacotherapy
• Classic Dopamine blockers
–
–
–
–
Act on D2 receptors
Reduce for positive symptoms
Do not reduce negative symptoms (might increase them)
Side effects:
• Tardive dyskinesia due to DA receptors up regulation in basal ganglia
• increase hypofrontality?
• Atypical (2nd generation) DA blockers
– Partial agonist
Partial agonist:
- High affinity
- Low activation
In frontal lobe:
- Acts as agonist
In n. accumbens
- Acts as antagonist
Pharmacotherapy (cont’d)
• Glutamatergic drugs (clinical trials)
– Glycine:
• It’s a NT necessary for opening NMDA channel
• Improves negative symptoms
Many unsolved mysteries…
• Ketamine
–
–
–
–
Similar to PCP
It is used for anesthesia in kids
Not used in adults because it can cause psychosis
Are kids’ brains unaffected, or are they more resilient?
(if the latter, would we find increase schizophrenia?)
• Why does dopamine cause positive symptoms?
– (S. Kapur)
… and some lessons for life
•
•
•
•
Flu Vaccine
Reduce maternal stress (physical & psychological)
Reduce teenager’s stress
Raise concern about friend/relative when you deem doing
so is warranted.
• Support early treatment (when onset is evident)
Summary
Spare slides
Pre-morbid development
• Schizotypal personality disorder at adolescence
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–
–
–
–
Social anxiety
Affective abnormalities
Eccentric behavior
Unusual ideas (e.g., persistent belief in ESP)
Unusual sensory experiences
• (not strong enough to be delusions or hallucinations)
• Relation between SPD and schizo (20-40% of SPD -> schizo),
familial link
• http://www.sfnsw.org.au/schizophrenia/sym
ptoms.htm
• http://www.emory.edu/EMORY_MAGAZI
NE/spring2000/inquiry.html